Biphenyl-5-alkanoic acid derivatives and use thereof

ABSTRACT

Compounds represented by general formula I or salts thereof, wherein n is an integer of 2 or 3; R represents a straight-chain or branched saturated alkyl group having 4 or 4 carbon atoms, a cyclopentyl group, a cyclohexyl group or the like, Y represents a hydroxyl or amino group, A represents a hydrogen atom, a hydroxyl, methoxy, nitro group or the like, Q represents a hydrogen atom or a hydroxyl or methoxy group. They can be formulated to give pharmaceutical compositions that are effective as prophylactic or therapeutic agents for allergic diseases associated with IgE production inhibitors or IgE antibodies.

This application is a 371 of PCT JP/98/04456 Oct. 2, 1998

FILED OF THE INVENTION

This invention relates to novel biphenyl-5-alkanoic acid derivatives orsalt thereof and a pharmaceutical composition containing the same as anactive ingredient, especially IgE antibody production suppressor anddrugs for treatment and prevention of allergic diseases characterized byIgE antibody suppressive action.

PRIOR ARTS

Allergic diseases such as bronchial asthma, allergic rhinitis, atopicdermatitis, allergic conjunctivitis and anaphylaxis are classified intotype I allergic reaction. The type I allergic reaction consists of,generally, the following three steps during the process of generation.Namely, these are: (1) the first step: antigen is entered into the body,and immunoglobulin E (IgE) is produced as a result of interaction withantigen-presenting cells such as macrophage, T cells and B cells, thenthe IgE antibody is bound with receptor on the cell membrane of mastcells and basophils to establish sensitization; (2) the second step: thereentry of antigen results to bind with IgE which is bound with thereceptor, to generate degranulation of mast cells or basophils byantigen-antibody reaction to release chemical mediators such ashistamine and SRS-A; and (3) the third step: the released chemicalmediators induce contraction of the smooth muscle, capillaryhyperpermeability and increase in mucous secretion to lead allergicreaction.

As above explained, the type I allergic reaction has known to be inducedby IgE antibody production, and, in fact, serum or tissue levels of IgEantibody in patients with the aforementioned allergic diseases showed,in most cases, higher than those of the healthy subjects. Consequently,a compound, which selectively suppresses IgE antibody production, mightbe a useful agent for causal therapy of allergic diseases, anddevelopment of such a compound and its pharmaceutical product has beendesired.

The known example of compound, which has similar structure of thecompound of the present invention, is, for example,3-(2-methoxy-1,1′-biphenyl-5-yl)propionic acid (J. Am. Chem. Soc.,75:2334, 1953) as choleretic agent. The said compound has differentstructure from the compound of the present invention in the ether moietyin phenolic hydroxy group in its structure, and in addition, noinformation on an action of IgE antibody production is disclosed. Thesame report discloses 3-(3-phenyl-4-methoxybenzoyl)propionic acid,however the said compound is different from the compound of the presentinvention in the ether moiety, furthermore a part of an oxo group inmethylene moiety between biphenyl moiety and carboxy group is differentin each other.

In the reference, Chem. Pharm. Bull. 35(5):1755, 1987, discloses methyl3-(4′-allyloxy-2-benzyloxy-1,1′-biphenyl-5-yl)propionate is disclosed,however it is different from ether moiety from the compound of thepresent invention. In addition, the said compound was synthesized as anintermediate of a natural compound magaldehyde and no pharmacologicalaction was disclosed. Further, in the said reference, on page 1762,methyl 3-(2,4′-dihydroxy-1,1′-biphenyl-5-yl)propionate and methyl3-(4′-allyloxy-2-hydroxy-1,1′-biphenyl-5-yl)propionate were reported,however it was different in its ether moiety from the compound of thepresent invention, furthermore no pharmacological action has reported.

DE-4019307 and Japanese Patent Unexamined Publication No. Hei 4-230252disclose methyl2-methoxyimino-3-(4′-chloro-2-methoxy-1,1′-biphenyl-5-yl)propionate asharmful organisms preventive agent. The said compound is different fromthe compound of the present invention in the structure on the pointshaving different structure in the ether moiety and having methoxyiminogroup in methylene moiety between biphenyl moiety and carboxy group. Inaddition, no action about IgE antibody production is disclosed.

DE-2513157 and Japanese Patent Unexamined Publication No. Sho 50-135050disclose methyl 4-oxo-4-(2-methoxy-1,1′-biphenyl-5-yl)-2-methylenebutyric acid as anti-inflammatory agent. The said compound is differentfrom the compound of the present invention on the point that it hasether moiety and has oxo group and methylene group in the methylenemoiety between biphenyl moiety and carboxy group. In addition, no IgEproduction is disclosed.

In Japanese Patent Unexamined Publication No. Sho 58-55469 describes3-(3-t-butoxy-2-hydroxy-1,1′-biphenyl-5-yl)propionic acid as astabilizer for resin. The said compound is different from the compoundof the present invention on the point of substituents in the ethermoiety and biphenyl moiety. Further, no pharmacological action isdisclosed.

J. Med. Chem. 11:1139, 1968, discloses4-(4-butoxy-1,1′-biphenyl-5-yl)-3-hydroxy butyric acid asanti-inflammatory agent. The said compound is different from thecompound of the present invention on the point of position ofsubstituent in ether moiety and having hydroxy group in methylene moietybetween biphenyl moiety and carboxy group. Further, no IgE antibodyproduction is disclosed.

In Japanese Patent Unexamined Publications No. Hei 4-95025 and No. Hei4-95049 disclose biphenyl-5,5′-bis-alkanoic acid derivative as an aldosereductase inhibitor. The said compound is different from the compound ofthe present invention on the point having alkanoic acid in both ofbenzene rings in biphenyl moiety. Further, no IgE antibody production isdisclosed.

U.S. Pat. No. 5,391,817 and Japanese Patent Unexamined Publication No.Hei 7-223997 disclose biphenyl derivatives as biaryl phospholipase A₂inhibitor. The said compounds are different from the compound of thepresent invention on the point of ether moiety and no compound of thepresent invention is included in their claims. Further, no IgE antibodyproduction is disclosed in these patents.

Problems to be Solved by the Invention

An aspect of the present invention is to provide a compound fortreatment and prevention of allergic diseases caused by type I allergicreaction, which is suppressed by selectively suppressing IgE antibodyproduction.

Means for Solving the Problems

In order to solve the above problems, we have extensively studied andfound that the novel compound biphenyl-5-alkanoic acid derivativesrepresented by the general formula shown below have selective andsuperior suppressive action against IgE antibody production, thencompleted the present invention.

An object of the present invention is to provide a compound of thegeneral formula (I) or salt thereof.

wherein n is an integer of either 2 or 3, R is straight or branchedsaturated alkyl of carbon numbers 4 or 5 (a), cyclopentyl, cyclohexyl,cyclopentylmethyl, cyclohexylmethyl or —(CH₂)_(m)W, proviso thatsaturated alkyl (a) may optionally be substituted by hydroxy, oxo orhalogen, m is an integer of 1-3, W is carboxy or —CONR¹R², in which R¹and R² are in together or each separately hydrogen or lower alkyl ofC₁₋₄, Y is hydroxy or amino, A is hydrogen, hydroxy, methoxy, nitro or—NHZ, in which Z is —CO R³ or —SO₂ R⁴, in which R³ is hydrogen,saturated alkyl (b) of C₁₋₄ or —NR⁵ ₂, the saturated alkyl (b) mayoptionally be substituted by hydroxy or halogen, R⁴ is saturated alkyl(c) of C₁₋₄ or —NR⁶ ₂, the saturated alkyl (c) may optionally besubstituted by halogen, R⁵ and R⁶ are hydrogen or lower alkyl of C₁₋₄,and Q is hydrogen, hydroxy or methoxy [hereinafter sometimes designatesas “the compound (I)”].

Another object of the present invention is to provide a drug comprisingthe compound of the above general formula (I) or pharmacologicallyacceptable salt thereof as an active ingredient.

In the above general formula (I), n is defined as any one of integer of2 or 3. No effect is obtained wherein n is 1 or 4. Since it is extremelycharacteristics when n is 2 or 3, ethylene in 2 or trimethylene in 3 ispreferable.

A group R is defined as straight or branched saturated alkyl of carbonnumbers 4 or 5 (a), cyclopentyl, cyclohexyl, cyclopentylmethyl,cyclohexylmethyl or —(CH₂)_(m)W, proviso that saturated alkyl (a) mayoptionally be substituted by hydroxy, oxo or halogen, and m is aninteger of 1-3, and W is carboxy or —CONR¹R², in which R¹ and R² are intogether or each separately hydrogen or lower alkyl of C₁₋₄.

In a group R, examples of straight or branched saturated alkyl of carbonnumbers 4 or 5 are n-butyl, isobutyl, 1-methylpropyl, t-butyl, n-pentyl,isopentyl, 2-methylbutyl and 1-methylbutyl. Among them, n-butyl,isobutyl, n-pentyl, and isopentyl are preferable, and n-butyl is mostpreferable.

In a group R, examples of straight or branched saturated alkyl of carbonnumbers 4 or 5 substituted by hydroxy are straight or branched saturatedalkyl of carbon numbers 4 or 5 substituted by a hydroxy in any carbonsexcept for carbon constituting ether bonding in the saturated alkyl.Examples are 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl,2-hydroxypentyl, 3-hydroxypentyl, 4-hydroxypentyl and 5-hydroxypentyl.Among them, 2-hydroxybutyl and 3-hydroxybutyl are preferable.

In a group R, examples of straight or branched saturated alkyl of carbonnumbers 4 or 5 substituted by oxo are straight or branched saturatedalkyl of carbon numbers 4 or 5 substituted by an oxo in a secondarycarbon except for carbon constituting ether bonding in the saturatedalkyl. Examples are 2-oxobutyl and 2-oxopentyl, and 2-oxobutyl is apreferable example.

A “halogen” in a group R of straight or branched saturated alkyl ofcarbon numbers 4 or 5 substituted by halogen means fluorine, chlorine,bromine or iodine. Examples of straight or branched saturated alkyl ofcarbon numbers 4 or 5 substituted by halogen are straight or branchedsaturated alkyl of carbon numbers 4 or 5 substituted by 1-3 halogens inany carbons except for carbon constituting ether bonding in thesaturated alkyl. Examples are 2-chlorobutyl, 3-chlorobutyl,2-chloropentyl, 3-chloropentyl, 4-chloropentyl, 5-chloropentyl,4-bromobutyl and 4,4,4-trifluorobutyl. 3-chlorobutyl and4,4,4-trifluorobutyl are preferable.

In a group R, cyclopentyl, cyclohexyl, cyclopentylmethyl andcyclohexylmethyl are preferable, and cyclohexylmethyl is mostpreferable.

In a group R, wherein R is —(CH₂)_(m)W, m is preferably integers of 1-3,especially methylene, in which m is 1, is preferable. W is mostpreferably a carboxy. When W is —CONR¹R², examples of R¹ and R² arehydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl andt-butyl, and R¹ and R² can be the same or different. Among them,hydrogen, methyl and ethyl are preferable, and hydrogen is mostpreferable. Consequently, when W is —CONR¹R², preferable examples arecarbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyland N,N-diethylcarbamoyl, and among them, carbamoyl is most preferable.

Examples of —(CH₂)_(m)W are carboxymethyl, 2-carboxyethyl,3-carboxypropyl, carbamoylmethyl, 2-carbamoylethyl, 3-carbamoylpropyl,(N-methylcarbamoyl)methyl, (N-ethylcarbamoyl)methyl,(N,N-dimethylcarbamoyl)methyl, (N,N-diethylcarbamoyl)methyl,2-(N,N-dimethylcarbamoyl)ethyl and 3-(N,N-dimethylcarbamoyl)propyl.Among them, carboxymethyl, 2-carboxyethyl, 3-carboxypropyl,carbamoylmethyl, and (N,N-dimethylcarbamoyl)methyl are preferable,especially carboxymethyl and carbamoylmethyl are most preferable.

When R contains asymmetric carbon, in case of one asymmetric carbon, twooptical isomers, and in case of two asymmetric carbons, four opticalisomers can be possible. Any these isomers are preferable examples. In amixture thereof, it is preferable for easier production.

A group Y is defined as hydroxy or amino, and any substituents arepreferable.

A group A is hydrogen, hydroxy, methoxy, nitro or —NHZ, in which Z is—COR³ or —SO₂ R⁴, in which R³ is hydrogen, saturated alkyl (b) of C₁₋₄or —NR⁵ ₂. The saturated alkyl (b) may optionally be substituted byhydroxy or halogen. R⁵ is hydrogen or lower alkyl of C₁₋₄. R⁴ issaturated alkyl (c) of C₁₋₄ or —NR⁶ ₂. The saturated alkyl (c) mayoptionally be substituted by halogen. R⁶ is hydrogen or lower alkyl ofC₄. Any substituents are preferable for the group A, and especiallyhydrogen is most preferable substituent.

When the group A is —NHZ and Z is —COR³, a group R³ is, for example,preferably hydrogen. When the group R³ is saturated alkyl (b) of C₁₄,the saturated alkyl (b) may optionally have branched chain, and examplesthereof are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl andt-butyl. Among them, methyl and ethyl are preferable, and methyl is mostpreferable. In the saturated alkyl (b), any carbons in the saturatedalkyl may optionally be substituted by one hydrogen. Examples thereofare hydroxymethyl and 2-hydroxyethyl, and hydroxymethyl is preferable.In the saturated alkyl (b), any carbons in the saturated alkyl mayoptionally be substituted by 1-3 halogens. Examples thereof arechloromethyl and trifluoromethyl, and chloromethyl is preferable. WhenR³ is —NR⁵ ₂, the group R⁵ is hydrogen, methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl and t-butyl. Among them, hydrogen andmethyl are preferable, and hydrogen is most preferable.

Examples of —NR⁵ ₂ are amino, dimethylamino and diethylamino. Amongthem, amino and dimethylamino are preferable, and amino is mostpreferable. Consequently, preferable examples of —COR³ are formyl,acetyl, propionyl, hydroxyacetyl, chloroacetyl, carbamoyl andN,N-dimethylcarbamoyl. Among them, formyl, acetyl and carbamoyl are mostpreferable examples.

When a group A is —NHZ and the group Z is —SO₂R⁴, in which R⁴ issaturated alkyl (c) of C₁₋₄, the saturated alkyl (c) may optionally havebranched chain. Examples thereof are methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl and t-butyl, and among them, methyl is mostpreferable. In the saturated alkyl (c), any carbons in the saturatedalkyl may optionally be substituted by 1-3 halogens, and examplesthereof are chloromethyl and trifluoromethyl. When R⁴ is —NR⁶ ₂, thegroup R⁶ is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl and t-butyl, and methyl are preferable.

Examples of —NR⁶ ₂ are amino, dimethylamino and diethylamino, and amongthem, dimethylamino is preferable. Consequently, examples of the group—SO₂R⁴ are methylsulfonyl, ethylsulfonyl, chloromethylsulfonyl,trifluoromethylsulfonyl, sulfamoyl and N,N-dimethylsulfamoyl. Amongthem, preferable examples are methylsulfonyl and N,N-dimethylsulfamoyland methylsulfonyl is most preferable.

Preferable examples of —NHZ in the group A are formylamino, acetylamino,propionylamino, hydroxyacetylamino, chloroacetylamino, carbamoylamino,N,N-dimethylcarbamoylamino, methylsulfonylamino andN,N-dimethylsulfamoylamino. Among them, formylamino, acetylamino,carbamoylamino and methylsulfonylamino are most preferable.

A group Q is defined as hydrogen, hydroxy or methoxy, and anysubstituents are most preferable.

Preferable scope of the compound of the present invention is a compoundin the general formula (I), wherein n is integer of 2 or 3, R isn-butyl, isobutyl, n-pentyl, isopentyl, cyclopentyl, cyclohexyl,cyclopentylmethyl, cyclohexylmethyl, 2-hydroxybutyl, 3-hydroxybutyl,2-oxobutyl, 3-chlorobutyl, 4,4,4-trifluorobutyl, carboxymethyl,2-carboxyethyl, 3-carboxypropyl, carbamoylmethyl or(N,N-dimethylcarbamoyl)methyl, Y is hydroxy or amino, A is hydrogen,hydroxy, methoxy, nitro, formylamino, acetylamino, propionylamino,hydroxyacetylamino, chloroacetylamino, carbamoylamino,N,N-dimethylcarbamoylamino, methylsulfonylamino, orN,N-dimethylsulfamoylamino, and Q is hydrogen, hydroxy or methoxy, orsalt thereof.

More preferable scope of the compound of the present invention includesa compound in the general formula (I), wherein n is integer of 2 or 3, Ris n-butyl, cyclohexylmethyl, carboxymethyl or carbamoylmethyl, Y ishydroxy or amino, A is hydrogen, formylamino, acetylamino,carbamoylamino or methylsulfonylamino, and Q is hydrogen, hydroxy ormethoxy, or salt thereof.

The most preferable scope of the compound of the present inventionincludes a compound in the general formula (I), wherein n is 2, R iscyclohexylmethyl, Y is hydroxy or amino, A is hydrogen, formylamino,acetylamino, carbamoylamino or methylsulfonylamino, and Q is hydrogen,hydroxy or methoxy, or salt thereof.

Concrete examples of the compound of the present invention (I) can bementioned as follows.

3-(2-butoxy-1,1′-biphenyl-5-yl)propionic acid;

3-(2-isobutoxy-1,1′-biphenyl-5-yl)propionic acid;

3-(2-pentyloxy-1,1′-biphenyl-5-yl)propionic acid;

3-(2-cyclopentyloxy-1,1′-biphenyl-5-yl)propionic acid;

3-(2-cyclohexyloxy-1,1′-biphenyl-5-yl)propionic acid;

3-(2-cyclopentylmethyloxy-1,1′-biphenyl-5-yl)propionic acid;

3-(2-cyclohexylmethyloxy-1,1′-biphenyl-5-yl)propionic acid;

3-[2-(2-hydroxybutyloxy)-1,1′-biphenyl-5-yl]propionic acid;

3-[2-(2-oxobutyloxy)-1,1′-biphenyl-5-yl]propionic acid;

3-(2-carboxymethyloxy-1,1′-biphenyl-5-yl)propionic acid;

3-(2-carbamoylmethyloxy-1,1′-biphenyl-5-yl)propionic acid;

3-(2-butoxy-3-nitro-1,1′-biphenyl-5-yl)propionic acid;

3-(3-acetylamino-2-butoxy-1,1′-biphenyl-5-yl)propionic acid;

3-(2-butoxy-3-methylsulfonylamino-1,1′-biphenyl-5-yl)propionic acid;

3-(3-acetylamino-2-cyclohexylmethyloxy-1,1′-biphenyl-5-yl)propionicacid;

3-(2-cyclohexylmethyloxy-3-methylsulfonylamino-1,1′-biphenyl-5-yl)propionicacid;

3-(2-cyclohexylmethyloxy-3-hydroxyacetylamino-1,1′-biphenyl-5-yl)propionicacid;

3-[2-cyclohexylmethyloxy-3-(N,N-dimethylcarbamoylamino)-1,1′-biphenyl-5-yl]propionicacid;

3-[2-cyclohexylmethyloxy-3-(N,N-dimethylsulfamoylamino)-1,1′-biphenyl-5-yl]propionicacid;

3-(3-carbamoylamino-2-cyclohexylmethyloxy-1,1′-biphenyl-5-yl)propionicacid;

3-(2-cyclohexylmethyloxy-3-methoxy-1,1′-biphenyl-5-yl)propionic acid;

3-(2-cyclohexylmethyloxy-3-hydroxy-1,1′-biphenyl-5-yl)propionic acid;

3-(2-cyclohexylmethyloxy-4′-hydroxy-1,1′-biphenyl-5-yl)propionic acid;

3-(2-cyclohexylmethyloxy-4′-methoxy-1,1′-biphenyl-5-yl)propionic acid;

3-(2-cyclohexylmethyloxy-4,1′-biphenyl-5-yl)propionamide;

4-(2-butoxy-1,1′-biphenyl-5-yl)butyric acid;

4-(2-isobutoxy-1,1′-biphenyl-5-yl)butyric acid;

4-[2-(-methylpropyloxy)-1,1′-biphenyl-5-yl]butyric acid;

4-(2-pentyloxy-1,1′-biphenyl-5-yl)butyric acid;

4-[2-(1-methylbutyloxy)-1,1′-biphenyl-5-yl]butyric acid;

4-[2-(2-methylbutyloxy)-1,1′-biphenyl-5-yl]butyric acid;

4-(2-isopentyloxy-1,1′-biphenyl-5-yl)butyric acid;

4-(2-cyclopentyloxy-1,1′-biphenyl-5-yl)butyric acid;

4-(2-cyclohexyloxy-1,1′-biphenyl-5-yl)butyric acid;

4-(2-cyclopentylmethyloxy-1,1′-biphenyl-5-yl)butyric acid;

4-(2-cyclohexylmethyloxy-1,1′-biphenyl -5-yl)butyric acid;

4-[2-(4-hydroxybutyloxy)-1,1′-biphenyl-5-yl]butyric acid;

4-[2-(3-hydroxybutyloxy)-1,1′-biphenyl-5-yl]butyric acid;

4-[2-(2-hydroxybutyloxy)-1,1′-biphenyl-5-yl]butyric acid;

4-(2-carboxymethyloxy-1,1′-biphenyl-5-yl)butyric acid;

4-[2-(2-carboxyethyloxy)-1,1′-biphenyl-5-yl]butyric acid;

4-[2-(3-carboxypropyloxy)-1,1′-biphenyl-5-yl]butyric acid;

4-(2-carbamoylmethyloxy-1,1′-biphenyl-5-yl)butyric acid;

4-[2-(N,N-dimethylcarbamoylmethyloxy)-1,1′-biphenyl-5-yl]butyric acid;

4-[2-(N,N-diethylcarbamoylmethyloxy)-1,1′-biphenyl-5-yl]butyric acid;

4-(2-butoxy-3-nitro-1,1′-biphenyl-5-yl)butyric acid;

4-(2-butoxy-3-formylamino-1,1′-biphenyl-5-yl)butyric acid;

4-(3-acetylamino-2-butoxy-1,1′-biphenyl-5-yl)butyric acid;

4-(2-butoxy-3-methylsulfonylamino-1,1′-biphenyl-5-yl)butyric acid;

4-(2-butoxy-3-methoxy-1,1′-biphenyl-5-yl)butyric acid;

4-(2-butoxy-1,1′-biphenyl-5-yl)butyramide;

4-(2-carbamoylmethyloxy-1,1′-biphenyl-5-yl)butyramide;

4-[2-(3-carbamoylpropyloxy)-1,1′-biphenyl-5-yl]butyramide;

4-[2-(4-chlorobutyloxy)-1,1′-biphenyl-5-yl]butyric acid;

4-[2-(3-chlorobutyloxy)-1,1′-biphenyl-5-yl]butyric acid;

4-[2-(4-bromobutyloxy)-1,1′-biphenyl-5-yl]butyric acid; and

4-[2-(4,4,4-trifluorobutyloxy)-1,1′-biphenyl-5-yl]butyric acid;

Among them, compounds having optical isomer are as follows.

3-[2-(2-hydroxybutyloxy)-1,1′-biphenyl-5-yl]propionic acid;

4-[2-(1-methylpropyloxy)-1,1′-biphenyl-5-yl]butyric acid;

4-[2-(1-methylbutyloxy)-1,1′-biphenyl-5-yl]butyric acid;

4-[2-(2-methylbutyloxy)-1,1′-biphenyl-5-yl]butyric acid;

4-[2-(3-hydroxybutyloxy)-1,1′-biphenyl-5-yl]butyric acid;

4-[2-(2-hydroxybutyloxy)-1,1′-biphenyl-5-yl]butyric acid; and

4-[2-(3-chlorobutyloxy)-1,1′-biphenyl-5-yl]butyric acid.

These optical isomers and mixtures thereof are preferable examples ofthe compound (I).

The specifically preferable compounds (I) of the present invention canbe listed as follows.

3-(2-butoxy-1,1′-biphenyl-5-yl)propionic acid;

3-(2-cyclohexylmethyloxy-1,1′-biphenyl-5-yl)propionic acid;

3-(2-carboxymethyloxy-1,1′-biphenyl-5-yl)propionic acid,

3-(2-carbamnoylmethyloxy-1,1′-biphenyl-5-yl)propionic acid;

3-(3-acetylamino-2-butyloxy-1,1′-biphenyl-5-yl)propionic acid;

3-(2-butoxy-3-methylsulfonylamino-1,1′-biphenyl-5-yl)propionic acid;

3-(3-acetylamino-2-cyclohexylmethyloxy-1,1′-biphenyl-5-yl)propionicacid;

3-(2-cyclohexylmethyloxy-3-methylsulfonylamino-1,1′-biphenyl-5-yl)propionicacid;

3-(3-carbamoylamino-2-cyclohexylmethyloxy-1,1′-biphenyl-5-yl)propionicacid;

3-(2-cyclohexylmethyloxy-4′-hydroxy-1,1′-biphenyl-5-yl)propionic acid;

3-(2-cyclohexylmethyloxy-4′-methoxy-1,1′-biphenyl-5-yl)propionic acid;

3-(2-cyclohexylmethyloxy-1,1′-biphenyl-5-yl)propionamide;

4-(2-butoxy-1,1′-biphenyl-5-yl)butyric acid;

4-(2-cyclohexyloxy-1,1′-biphenyl-5-yl)butyric acid;

4-(2-carboxymethyloxy-1,1′-biphenyl-5-yl)butyric acid;

4-(2-carbamoylmethyloxy-1,1′-biphenyl-5-yl)butyric acid;

4-(2-butoxy-3-formylamino-1,1′-biphenyl-5-yl)butyric acid;

4-(3-acetylamino-2-butoxy-1,1′-biphenyl-5-yl)butyric acid

4-(2-butoxy-3-methylsulfonylamino-1,1′-biphenyl-5-yl)butyric acid;

4-(2-butoxy-1,1′-biphenyl-5-yl)butyramide; and

4-(2-carbamnoylmethyloxy-1,1′-biphenyl-5-yl)butyramide.

Salt of the compound (I) is preferably pharmaceutically acceptable salt,and in case that Y is hydroxy; W is carboxy; or A or Q is phenolichydroxy, it means salt of any one or more of these groups. One to fouralkaline salts can be formed depending on numbers of acidic groups, andexamples of salt are salt with inorganic base such as sodium andammonium, or organic base such as triethylamine.

The compound (I) of the present invention can be produced, for example,by the following various methods.

[The Process for Production 1]

(Process a)

A Compound of the General Formula II, which is the compound (I) of thepresent invention, wherein Y is hydroxy;

wherein n, R, A and Q have the same meaning hereinbefore, [hereinafterdesignates as simply “the compound (II)”]can be produced by hydrolyzinga compound of the general formula (III) [hereinafter designates assimply “the compound (III)”]

wherein R′ is a straight or branched saturated alkyl of C₄ or C₅ (a′),cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclohexylmethyl or—(CH₂)_(m)W, proviso that in the saturated alkyl (a′), any carbonsexcept for carbon constructing the ether bond may optionally besubstituted by one of hydroxy or acetoxy; secondary carbon except forcarbon constructing the ether bond may optionally be substituted by oneof oxo; or any carbons except for carbon constructing the ether bond mayoptionally be substituted by 1-3 halogens; W is —CONR¹R² oralkyloxycarbonyl which can be converted to carboxy by hydrolysis, ornitrile; Y′ is lower alkoxy such as methoxy or ethoxy; Al is hydrogen,hydroxy, methoxy, nitro or —NHZ′, in which Z′ is —COR³′ or —SO₂R⁴,R³′ ofwhich is hydrogen or saturated alkyl of C₁₋₄ (b′) or —NR⁵ ₂; any carbonsin the saturated alkyl (b′) may optionally be substituted by one ofacetoxy or 1-3 halogens; Q¹ is hydrogen, hydroxy, methoxy, acetoxy orbenzoyloxy; and n, m, R¹, R², R⁴ and R⁵ have the same meaningshereinbefore, with base in a polar solvent, converting a group Y′ tohydroxy, and simultaneously converting, if those groups exist, acetoxyin the saturated alkyl (a′) to hydroxy, alkyloxycarbonyl or nitrile inW′ to carboxy, acetoxy in the saturated alkyl (b′) to hydroxy, oracetoxy or benzoyloxy in the group Q to hydroxy.

Examples of base used herein are alkaline metal salt such as sodiumhydroxide, potassium hydroxide, sodium carbonate, potassium carbonate,sodium methoxide and potassium t-butoxide, and organic base such astriethylamine. Amount of use thereof is, generally, 1-20 molar excess incase of alkaline metal salt, preferably 1-10 molar excess, and equimolarto large excess in case of organic base.

Examples of polar solvent are water, methanol, ethanol, tetrahydrofuranand dioxane, and these can be used by mixing if necessary. Reactiontemperature can be selected within suitable temperature from roomtemperature to reflux temperature of the solvent. Reaction time isusually 0.5-72 hours when alkaline metal salt is used, preferably 1-48hours, and when organic base is used, it is usually from 5 hours to 14days. The reaction process can be traced by thin layer chromatography(TLC) and high performance liquid chromatography (HPLC), consequently,the reaction can be terminated when the yield of the compound (II)reaches to maximum.

The thus obtained compound (II) can be isolated from the reactionmixture in the stage of free carboxyic acid, in case of the polarsolvent being aqueous solvent, by distilling the solvent, neutralizingwith inorganic acid such as hydrochloric acid, dissolving the residuewith non-aqueous solvent, washing with weak acidic aqueous solution orwater, and removing the solvent. In case that the polar solvent isnon-aqueous solvent, the compound (II) can be isolated by neutralizingthe reaction mixture, washing with water and removing the solvent.

In case that, after reaction, the compound (II) is solidified by formingsalt with using base, salt of the compound (II) can be obtained byisolating it with conventional manner and being purified.

[The Process for Production 2]

(Process b-1)

A compound of the general formula (IV), which is the compound (I) of thepresent invention, wherein Y is amino and R is —(CH₂)_(m)COOH;

wherein R″ is straight or branched saturated alkyl of C4 or C5 (a),cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclohexylmethyl or—(CH₂)_(m)CONR¹R², n, m, A, Q, R¹, R² and saturated alkyl (a) have thesame meanings hereinbefore [hereinafter simply designates as “compound(IV)”], can be produced by reacting, for example, the compound (II)hereinbefore with inorganic halogenide without presence of solvent or inan inert solvent to convert acid halogenide, which is then reacting withexcess concentrated aqueous ammonia directly or dissolved in an inertsolvent.

Examples of inorganic halogenide are thionyl chloride, phosphorylchloride, phosphorus pentachloride and phosphorus trichloride, and amongthem, thionyl chloride is preferable. Amount of halogenide to be used isgenerally equivalent to large excess for the compound (II), preferably1.5-5 molar excess. Examples of inert solvent are halogenatedhydrocarbon such as dichloromethane, chloroform and 1,2-dichloroethane,ether such as tetrahydrofuran and dioxane and benzenes such as benzene,toluene, xylene and chlorobenzene. These solvents can be used alone ormixture thereof. Catalytic amount of N,N-dimethylformamide canoptionally be added for stimulating the reaction. Reaction temperaturecan be selected generally at room temperature to reflux temperature ofthe solvent. Reaction time is usually 0.5-24 hours, preferably 1-6hours.

Examples of inert solvent used in a reaction with ammonia arehalogenated hydrocarbon such as dichloromethane, chloroform and1,2-dichloroethane, ether such as tetrahydrofuran and dioxane andbenzenes such as benzene, toluene, xylene and chlorobenzene. Reactiontemperature can be selected generally from −10° C. to room temperature.Reaction time is generally 0.5-24 hours, preferably 0.5-6 hours.

(Process b-2)

The compound (IV) can be produced according to a method described in NewExperimental Chemistry Series (Japan Chemical Society Ed., Maruzen Publ.Co.), Vol. 14, page 1147, Ammonolysis, in which the compound (III)hereinbefore is reacted in an excess amount of concentrated aqueousammonia in the presence of catalysis such as ammonium chloride, sodiummethoxide or butyl lithium.

(Process b-3)

The compound (I), wherein Y is amino and R is —(CH₂)_(m)COOH, i.e. acompound represented by the general formula (V)

wherein n, m, A and Q have the same meanings hereinbefore, [hereinaftersimply designates as “the compound (V)”] can be synthesized bysubjecting to amidation of the compound (III), wherein R is—(CH₂)_(m)COOBn, i.e. a compound (VI) of the formula,

wherein Bn is benzyl, and n, m, Y′, A and Q have the same meaningshereinbefore, [hereinafter simply designates as “the compound (VI)”],according to a method of ammonolysis shown in the above process b-2,then the benzyl ester is hydrogenated using hydrogen source such ashydrogen gas in the presence of catalysis such as palladium carbonpowder in an inert solvent such as methanol to convert carboxy.

The compound (III) [including the compound (VI)] used in the processes 1and 2 for production of the compound (I) can be produced by, forexample, the following methods 1-4 for synthesis of intermediates.

[Process for Production of Intermediate 1]

(Process c-1)

The compound (III), wherein A¹ and Q¹ are hydrogen, i.e. a compound(VII) of the general formula,

wherein n, R′ and Y′ have the same meanings hereinbefore, [hereinaftersimply designates as “the compound (VII)”], can be produced by reactingthe compound of the formula (VIII),

wherein n, and Y′ have the same meanings hereinbefore, [hereinaftersimply designates as “the compound (VIII)”], with the formula (IX),

R′—X  (IX)

wherein X is halogen such as chlorine, bromine and iodine or sulfatesuch as p-toluenesulfonyloxy, methanesulfonyloxy and(2,4,6-trimethylphenyl) sulfonyloxy (mesitylenesulfonyloxy), and R′ hasthe same meaning hereinbefore, (hereinafter simply designates as“alkylating agent”), in an inert solvent in the presence of suitablebase.

Examples of alkylating agent used herein are the straight or branchedalkyl halide of C₄ or C₅ such as alkyl iodide, alkyl bromide, alkylchloride or cyclohexylmethyl bromide, the haloalkane carboxylate such asbromoacetic acid ester and 4-bromobutyric acid ester, and the haloalkanecarboxamide such as bromoacetamide and chloroacetic acid dimethylamide,in all of which carbon except for carbon binding with halogen isoptionally substituted by an acetoxy, secondary carbon except for carbonbinding with halogen is optionally substituted by an oxo, or carbonexcept for carbon binding with halogen is optionally substituted by 1-3halogens, or the alkyl sulfate obtained by conventionally mesylated,tosylated or methylene sulfonylated straight or branched primary orsecondary alcohol or cyclopentylmethyl alcohol, or the alkyl sulfateobtained by that the commercially available alkyl diol of C₄ or C₅having primary and secondary hydroxy is conventionallymethylenesulfonylated the primary alcohol, then the secondary alcohol isconventionally protected by acetyl. Amount of use thereof is generallyequimolar to 40 molar excess, preferably equimolar to 10 molar excess,of the compound (VIII). Examples of inert solvent used in the reactionare alcohol such as methanol or ethanol, ether such as tetrahydrofuranor dioxane, benzens such as benzene, toluene or xylene,N,N-dimethylformamide, acetonitrile or acetone, and can be used ifnecessary with mixture thereof. Examples of base used herein are, forexample, alkaline metal such as sodium hydroxide, potassium hydroxide,sodium carbonate, potassium carbonate, sodium hydride, sodium methoxideand potassium t-butoxide, and tertiary organic amine such as pyridine,4-dimethylamino pyridine, 1,8-diazabicyclo [5,4,0]-undecene,trimethylamine and triethylamine. Amount of use thereof is generallyequimolar to 10 molar excess, preferably equimolar to 5 molar excess, ofthe compound (VIII). Reaction temperature can be selected withinsuitable temperature from room temperature to reflux temperature of thesolvent, preferably at room temperature to 80° C. Reaction time isusually 1 hour-6 days, preferably 2-48 hours. The reaction process canbe traced by thin layer chromatography (TLC) and high performance liquidchromatography (HPLC), consequently, the reaction can be terminated whenthe yield of the compound (VII) reaches to maximum. In case of slowreaction, 0.1-1.5 molar excess of catalyst such as potassium iodide orcopper powder can optionally be added.

(Process c-2)

The compound (VII) can be produced by the Mitsunobu reaction from thecompound (VIII) according to the reference (O. Mitsunobu, Synthesis,page 1, 1981). Namely, it can be obtained by reacting the compound(VIII) in organic solvent in the presence of phosphine such astriphenylphosphine and tributylphosphine and azo compound such asdiethyl azodicarboxyate, N,N,N′,N′-tetramethyl azodicarboxamide,1,1′-(azodicarbonyl) dipiperidine and N,N,N′,N′-tetraisopropylcarboxamide, with commercially available straight or branched primary orsecondary alcohol of C₄ or C₅, cyclopentyl alcohol, cyclohexyl alcoholor cyclopentylmethyl alcohol. Examples of solvent are ether such asdiethyl ether, tetrahydrofuran or dimethoxyethane, and benzens such asbenzene, toluene or xylene, and can be used if necessary with mixturethereof. Amount of phosphins used is generally equimolar to 10 molarexcess, preferably 1.5 to 5 molar excess, of the compound (VIII). Amountof azo compound used is generally equimolar to 10 molar excess,preferably 1.5 to 5 molar excess, of the compound (VIII). Reactiontemperature can be selected within suitable temperature from −20° C. toroom temperature, preferably at 0° C. to room temperature. Reaction timeis usually 3 hours-3 days, preferably 6-24 hours. The reaction processcan be traced by thin layer chromatography (TLC) and high performanceliquid chromatography (HPLC), consequently, the reaction can beterminated when the yield of the compound (VII) reaches to maximum.

(Process c-3)

The compound (VII), wherein R′ is 2-hydroxy alkyl of C₄ or C₅, can alsobe produced by reacting the compound (VIII) with the corresponding1,2-epoxy alkane such as 1,2-epoxy butane and 1,2-epoxy pentane in thepresence of base in an organic solvent. Amount of 1,2-epoxy alkane usedis generally equimolar to large excess, preferably 3 to 10 molar excess,of the compound (VIII). Examples of base used herein are, for example,alkaline metal such as sodium hydroxide, potassium hydroxide, sodiumcarbonate, potassium carbonate, sodium hydride, sodium methoxide andpotassium t-butoxide, and tertiary organic amine such as pyridine,4-dimethylamino pyridine, 1,8-diazabicyclo [5,4,0]-undecene,trimethylamine, triethylamine and diisopropylethylamine. Amount of usethereof is generally equimolar to large excess, preferably 3 to 20 molarexcess, of the compound (VIII).

Since this reaction needs for long time, it is preferably proceeded inthe autoclave. Examples of solvent used are alcohol such as methanol orethanol, ether such as tetrahydrofuran or dioxane, benzens such asbenzene, toluene or xylene, N,N-dimethylformamide, acetonitrile oracetone. Reaction temperature is generally at room temperature to 200°C. Reaction time is generally for 1 hour to 7 days.

(Process c-4)

The compound (VII), wherein R′ is —(CH₂)₂W, can be produced by reactingthe compound (VI) with acrylic acid derivative such as acrylate,acrylamide or acrylonitrile and base, if required adding coppercatalyst. Amount of acrylic acid derivative is generally 2 molar excessto large excess of the compound (VIII). Examples of base used in thisreaction are alkaline metal such as metallic sodium, sodium methoxideand potassium t-butoxide, tertiary ammonium such as toriton B(trimethylbenzyl ammonium hydroxide), and tertiary organic amine such astrimethylamine, triethylamine and isopropyl ethylamine. Examples ofcopper catalyst are cupric hydroxide and copper acetate hydrate. Amountused thereof is generally 0.1—equimolar of the compound (VIII). Reactioncan be proceeded generally in acrylic acid derivative as a solvent or inalcohol such as methanol and ethanol or benzenes such as benzene,toluene and xylene. Reaction time is usually 3-24 hours. The reactionprocess can be traced by thin layer chromatography (TLC) and highperformance liquid chromatography (HPLC), consequently, the reaction canbe terminated when the yield of the compound (VII) reaches to maximum.

(Process d)

The compound (VIII), wherein n is 2, can be produced by conventionallydemethylating the known 3-(2-methoxy-1,1′-biphenyl-5-yl)propionic aciddisclosed in the reference (R. R. Burtner et al. J. Am. Chem. Soc. 75:2334, 1953) and conventionally esterifying the carboxyic acid. Forexample, 3-(2-methoxy-1,1′-biphenyl-5-yl)propionic acid can be obtainedby reacting at about 180° C. in pyridine-hydrochloric acid complex toconvert methoxy to hydroxy, and reacting the thus obtained compound withthionyl chloride in alcohol such as methanol.

(Process d)

The compound (VIII), wherein n is 3, can be produced by demethylatingand esterifying the compound of the formula (X), [hereinafter simplydesignates as “the compound (X)”],

wherein Y″ is hydroxy or lower alkoxy such as methoxy and ethoxy,according to the same method described in the process d for productionof the intermediate 1.

(Process e)

The compound (X) can be produced by reducing a ketone carbonyl of theformula (XI), [hereinafter simply designates as “the compound (XI)”],

wherein Y″ has the same meaning hereinbefore, according to a methoddescribed in the reference (K. P. Mathai et al. J. Indian Chem. Soc. 42:86, 1965).

The compound (X) can also be produced by hydrogenating the compound (XI)by using hydrogen source such as hydrogen gas, ammonium formate andhydrazine hydride in inert solvent in the presence of catalyst. Examplesof inert solvent are alcohol such as methanol and ethanol, halogenatedhydrocarbon such as dichloromethane and 1,2-dichloroethane, ether suchas tetrahydrofuran and dioxane, and ethyl acetate, and these solvent canoptionally be used in a mixture thereof. Trace amount of acid such ashydrochloric acid and acetic acid can be added for stimulating thereaction. Catalyst used herein is palladium carbon powder, platinumoxide, and the like.

(Process f)

The compound (XI), wherein Y″ is hydroxy, i.e.3-(4-methoxy-3-phenylbenzoyl)propionic acid is a known compound in thereference (R. R. Burtner et al. J. Am. Chem. Soc. 75: 2334, 1953). Thecompound, wherein Y″ is lower alkoxy such as methoxy and ethoxy, can beproduced by reacting the commercially available 2-methoxy biphenyl with3-alkoxycarbonyl propionyl chloride in the presence of Lewis acidcatalyst in Friedel-Crafts reaction. Amount of acid chloride isgenerally 1-10 molar excess, preferably 1.5-4 molar excess of the rawmaterial. Examples of Lewis acid are aluminum chloride, tin chloride ortitanium chloride. Amount of these materials is generally 1-10 molarexcess, preferably 1-4 molar excess. Example of solvent used in thereaction is halogenized hydrocarbon such as dichloromethane and1,2-dichloroethane, nitrobenzene and carbon disulfide. Reactiontemperature is selected suitable temperature of generally at −10-100°C., preferably 0° C.—room temperature. Reaction time is usually 1-16hours, preferably 2-8 hours. The reaction process can be traced by thinlayer chromatography (TLC) and high performance liquid chromatography(HPLC), consequently, the reaction can be terminated when the yield ofthe compound (XI) reaches to maximum.

[Process for Production of Intermediate 2]

(Process d)

The compound (III), wherein any one of A¹ and Q¹ is hydrogen and n is 2,i.e. a compound (XII) of the general formula,

wherein A² and Q² are hydrogen or hydroxy, and at least one of them ishydroxy, and R′ and Y′ have the same meanings hereinbefore, [hereinaftersimply designates as “the compound (XII)”], can be produced by the sameprocess of demethylating and esterifying the compound of the formula(XIII),

wherein A³ is hydrogen or methoxy, and R′ and Y7 have the same meaningshereinbefore and at least one of them is other than hydrogen[hereinafter simply designates as “the compound (XIII)”], as shown inthe process for production of intermediate 1, process d.

(Process g)

The compound (XIII) can be produced by catalytic reaction of thecompound (XIV) of the formula,

wherein Q³ is hydrogen, methoxy or benzyloxy, R′, Y″ and A³ have samemeanings hereinbefore, [hereinafter simply designates as “the compound(XIV)”], as described in the chemical reference. For example, doublebond in the compound (XIV) is hydrogenated by using hydrogen source suchas hydrogen gas, ammonium formate and hydrazine hydride, in alcoholicsolvent such as methanol or ethyl acetate alone or with mixture, in thepresence of catalyst such as palladium carbon, and simultaneouslyconverting benzyloxy of Q³ to hydroxy, if it exists.

(Process h)

The compound (XIV) can be produced, for example, according to a methoddescribed in New Experimental Chemistry Series (Japan Chemical SocietyEd., Maruzen Publ. Co.), Vol. 14, page 238, Homer-Emmons reaction, fromthe compound (XV) of the formula (XV),

wherein R′, A³ and Q³ have same meanings hereinbefore and at least oneof A³ and Q³ is other than hydrogen, [hereinafter simply designates as“the compound (XV)”]. Namely, the compound (XV) is reacted with thecommercially available dialkyl phosphono acetic acid ester in inertsolvent, for example alcohol such as methanol and ethanol, or ether suchas tetrahydroftiran and dimethoxy ethane, in the presence of sodiumhydride or sodium alkoxide. Reaction temperature is generally at −10°C.—reflux temperature of the solvent, preferably at 0° C.—roomtemperature. Reaction time is generally at 1-16 hours, preferably at 2-8hours. The reaction process can be traced by thin layer chromatography(TLC) and high performance liquid chromatography (HPLC), consequently,the reaction can be terminated when the yield of the compound (XIV)reaches to maximum.

(Process i)

The compound (XV) can be produced from the compound (XVI) of theformula,

wherein X′ is bromine or iodine, and R′ and A³ have the same meaningshereinbefore, [hereinafter simply designates as “the compound (XVI)”]and the compound (XVII) of the formula,

wherein Q³ has the same meanings hereinbefore, [hereinafter simplydesignates as “the compound (XVII)”], according to the method describedin Experimental Chemistry Series, 4th Ed. (Japan Chemical Society Ed.,Maruzen Publ. Co.), Vol. 25, page 403, Suzuki reaction. Namely, thecompound can be obtained by reacting the compound (XVI) with thecompound (XVII) in solvent in the presence of catalyst prepared fromphosphine such as triphenyl phosphine, tri(o-toryl)phosphine,1,2-bis(diphenyl phosphino)ethane and1,1′-bis(diphenylphosphino)ferrocene and palladium complex such aspalladium acetate and trisdibenzylidene acetone palladium (O), ortetrakis(triphenylphosphine)palladium (O) catalyst, and base such aspotassium carbonate, sodium hydroxide or triethylamine. Examples ofsolvent are ether such as dioxane and dimethoxy ethane, benzens such asbenzene, toluene and xylene, N,N-dimethylformamide and water, ifnecessary mixture thereof. Amount of catalyst used is generally0.001—equimolar amount, preferably 0.01-0.10 molar excess of thecompound (XVI). Amount of base used is generally 1-20 molar excess,preferably 1-5 molar excess of the compound (XVI). Amount of thecompound (XVII) is generally 1-10 molar excess, preferably 1-5 molarexcess of the compound (XVI). Reaction temperature is generally at −10°C.—reflux temperature of the solvent, preferably at 0° C.—roomtemperature. Reaction time is generally at 1-24 hours, preferably at 2-8hours. The reaction process can be traced by thin layer chromatography(TLC) and high performance liquid chromatography (HPLC), consequently,the reaction can be terminated when the yield of the compound (XV)reaches to maximum. 4-benzyloxyphenyl boric acid in the compound (XVII)can be produced from the compound, which is produced by benzylatinghydroxy in the commercially available 4-bormophenol, according to thereference (Y. Satoh et al. Synthesis, page 1146, 1994).

Process c)

The compound (XVI) can be produced by etherifying3-bromo-4-hydroxybenzaldehyde, which is produced by conventionaldemethylation of the commercially available3-bromo-4-methoxybenzaldehyde described in the Chemical references, orthe commercially available 5-iodovanillin according to any methods shownin the prior process c in the production method of the intermediate 1.

[Process for Production of Intermediate 3]

(Process d)

The compound (III), wherein A′ or Q′ is hydroxy and n is 3, i.e. thecompound (XVIII)of the formula,

wherein R′, Y′, A² and Q² have the same meanings hereinbefore, and atleast either A² or Q² is hydroxy, [hereinafter simply designates as “thecompound (XVIII)”], can be produced by demethylating and esterifying thecompound of the formula (XIX),

wherein R′, Y″, A³ and Q have the same meanings hereinbefore, and atleast either A³ or Q is other than hydrogen, [hereinafter simplydesignates as “the compound (XIX)”], according to the same methoddescribed in the process d for production of the intermediate 1.

(Process e)

The compound (XIX) can be produced from the compound (XX) of theformula,

wherein R′, Y″, A³ and Q³ have the same meanings hereinbefore, and atleast either A³ or Q³ is other than hydrogen, [hereinafter simplydesignates as “the compound (XX)”], according to the same methoddescribed in the process e for production of the intermediate 1.

(Process f)

The compound (XX) can be produced from the compound (XXI) of theformula,

wherein R′, A³ and Q³ have the same meanings hereinbefore, and at leasteither A³ or Q³ is other than hydrogen, [hereinafter simply designatesas “the compound (XXI)”], according to the same method described in theprocess f for production of the intermediate 1.

(Process c)

The compound (XXI) can be produced from the compound (XXII) of theformula,

wherein A³ and Q³ have the same meanings hereinbefore, and at leasteither A³ or Q³ is other than hydrogen, [hereinafter simply designatesas “the compound (XXII)”], according to the same method described in theprocess c for production of the intermediate 1.

(Process j)

The compound (XXII) can be produced by conventional demethoxymethylationof the compound (XXIII) of the formula,

wherein A³ and Q³ have the same meanings hereinbefore, and at leasteither A³ or Q³ is other than hydrogen, [hereinafter simply designatesas “the compound (XXIII)”].

For example, the compound can be obtained by treating with acid such asphosphoric acid in the water miscible solvent such as dioxane.

(Process k)

The compound (XXIII) can be produced from the compound (XXIV) of theformula,

wherein A³ has the same meaning hereinbefore, [hereinafter simplydesignates as “the compound (XXIV)”], and the compound (XXV) of theformula,

wherein Q³ and X′ have the same meanings hereinbefore, according to themethod described in Experimental Chemistry Series, 4th Ed. (JapanChemical Society Ed., Maruzen Publ. Co.), Vol. 25, page 401,cross-coupling reaction. For example, after the compound (XXIV) islithiated by alkyl lithium such as n-butyl lithium and t-butyl lithium,the compound, which is subjected to metal exchange with zinc chloride,is reacted with the compound (XXV) in the presence of palladium catalystsuch as tetrakis(triphenylphosphine)(O).

The compound (XXIV) can be produced from the commercially availablephenol or 2-methoxy phenol and methoxymethyl chloride by the methodshown in the process 3, process c-1.

The compound (XXV), wherein Q³ is benzyloxy, can be produced by reactinghydroxy of the commercially available 4-bromophenol with benzyl halide.The other type of compound (XXV) can easily be obtained.

[Process for Production of Intermediate 4]

(Process 1-1)

The compound (III), wherein A¹ is —NHZ′, i.e. the compound of theformula (XXVI),

wherein Q⁴ is hydrogen, methoxy, acetoxy or benzoyloxy, n, R′, Y′ and Z′have the same meanings hereinbefore, can be produced by condensing thecompound of the formula (XXVII),

wherein n, R′, Y′ and Q⁴ have the same meanings hereinbefore,[hereinafter simply designates as “the compound (XXVII)”], in an inertsolvent with acylating agent such as acid anhydride, acid halide,N,N-dialkylcarbamoyl chloride, alkylsulfonyl chloride orN,N-dialkylsulfamoyl chloride, if necessary in the presence of base.Examples of inert solvent used herein are halogenated hydrocarbon suchas dichloromethane and chloroform, ether such as tetrahydrofuran,dioxane and diethyl ether, dimethyl sulfoxide, N,N-dimethylformamide andacetonitrile. These can be used alone or admixture.

Examples of acylating agent, for example, acid anhydride are aceticanhydride, propionic anhydride, butyric anhydride, isobutyric anhydride,pivalic anhydride and trifluoroacetic anhydride. Examples of acid halideare acetyl chloride, propionyl chloride, butyryl chloride, isobutyrylchloride, isovaleryl chloride, pivaloyl chloride, chloroacetyl chloride,acetoxyacetyl chloride and methoxyacetyl chloride. Examples ofN,N-dialkylcarbamoyl chloride are N,N-dimethylcarbamoyl chloride andN,N-diethylcarbamoyl chloride. Examples of sulfonic anhydride aretrifluoromethanesulfonic anhydride, etc. Examples of alkylsulfonylchloride are methylsulfonyl chloride and ethylsulfonyl chloride.Examples of N,N-dialkylsulfamoyl chloride are N,N-dimethylsulfamoylchloride, etc. Amount of use thereof is 1-20 molar excess, preferably1-10 molar excess of the compound (XXVII).

Examples of base used in the above reaction are alkaline metal such assodium hydrogen carbonate, sodium hydroxide, potassium carbonate, sodiumcarbonate, potassium hydroxide and sodium methylate, and organic aminesuch as pyridine, trimethylamine and triethylamine. Amount use thereofis generally 1-20 molar excess, preferably 1-10 molar excess of thecompound (XXVII).

Reaction temperature is generally at −30-120° C., preferably −20-50° C.Reaction time is generally at 0.5-72 hours, preferably at 0.5-48 hours.The reaction process can be traced by thin layer chromatography (TLC)and high performance liquid chromatography (HPLC), consequently, thereaction can be terminated when the yield of the compound (XXVI) reachesto maximum.

The compound (XXVI) hereinabove, wherein Z′ is formyl, can be producedby replacing the acylating agent in the above reaction to a mixture of99% formic acid and acetic anhydride.

(Process 1-2)

The compound (XXVI), wherein Z′ is carbamoyl, can be produced, forexample, by reacting the compound (XXVII) with 1-5 molar excess ofalkaline metal cyanate (such as NaOCN and KOCN) in a mixture of waterand acetic acid. Reaction temperature is generally at room temperature−100° C. The reaction time is 1-24 hours.

(Process m)

The compound (XXVII) can be produced by hydrogenating nitro group of thecompound (XXVIII) of the formula,

wherein n, R′, Y′ and Q⁴ have the same meanings hereinbefore,[hereinafter simply designates as “the compound (XXVIII)”], with theconventional method, for example, in a solvent such as methanol, in thepresence of catalyst such as palladium carbon powder or palladium oxide,at room temperature or heated temperature, or by reducing withhydrochloric acid in the presence of iron powder or tin (II) salt atroom temperature to reflux temperature.

(Process n)

The compound (XXVIII) can be produced by nitrating the compound (XXIX)of the formula,

wherein n, R′, Y′ and Q⁴ have the same meanings hereinbefore,[hereinafter simply designates as “the compound (XXIX)”], according tothe conventional method described in the chemical reference. Forexample, a mixture of 70-98% nitric acid and acetic anhydride solutionwas added to acetic anhydride solution of the compound (XXIX) andreacted at −20-5° C.

(Process o)

The compound (XXIX) can be produced by acetylating or benzoylating thecompound (XXX) of the formula,

wherein n, R′, Y′ and Q have the same meanings hereinbefore,[hereinafter simply designates as “the compound (XXX)”], according tothe conventional method. For example, the compound (XXX) is reacted withacetyl chloride or benzoyl chloride at 0° C.—room temperature.

The compound (I) of the present invention having assymetric carbon inthe substituent R can be isolated as optical isomer of the objectiveproduct or its precursor by conventional method. Such the methodsinclude a method of high performance liquid chromatography (HPLC) usingoptically active column (process p) and a method, in which the compoundis condensing with optically active compound, separating the produceddiastereoisomer and decomposing the same again. In case that theprecursor is isolated to form optical isomer, thereafter theaforementioned process is performed, then the optical isomer of theobjective compound (I) can be produced.

The compound (I) of the present invention having acidic functional groupsuch as carboxy and phenolic hydroxy can be converted topharmaceutically acceptable salt (such as inorganic salt with sodium orammonium, or organic salt with triethylamine) by conventional method.

In order to obtain inorganic salt, for example, the objective compound(I) is preferably dissolved in aqueous solution containing at leastequimolar amount of hydroxide, carbonate or bicarbonate corresponding tothe desired inorganic salt. In the reaction, water miscible inertorganic solvent such as methanol, ethanol, acetone and dioxane can bemixed. For example, when sodium hydroxide, sodium carbonate or sodiumbicarbonate is used, solution of sodium salt can be obtained.

In case that solid salt is required, the solution is evaporated, orslightly polar solvent of water miscible organic solvent such as butanolor ethylmethyl ketone is added to obtain solid salt.

The compounds described in the specification of the present inventioncan be purified by known methods such as recrystallization orchromatography (column chromatography, flush column chromatography, TLCand HPLC).

The compound (I) of the present invention and pharmaceuticallyacceptable salt thereof has no effect for production of immunoglobulin G(IgG), which is thought to be important for biological reaction such asprevention of infection, has selective suppressive action against IgEantibody production, and shows no death when administered orally 300mg/kg in rats. Consequently, it is safe compound for pharmaceuticals andis useful as an active ingredient of the pharmaceuticals. Preferable useof the compound (I) of the present invention as pharmaceuticals includessuppressive agent for IgE antibody production and drug for treatmentand/or prevention of allergic diseases caused by IgE antibody productionsuch as bronchial asthma, allergic rhinitis, atopic dermatitis, allergicconjunctivitis and anaphylaxis.

In order to use the compound (I) of the present invention orpharmaceutically acceptable salt thereof as the above pharmaceuticals,effective amount of the compound (I) or pharmaceutically acceptable saltthereof can be used directly or mixed with pharmaceutically acceptablecarrier to prepare pharmaceutical composition. Such the carrier can be asuspending agent such as carboxymethyl cellulose or purified water andphysiological saline, and other known carriers.

Examples of the pharmaceutical form for preparing formulation of theabove pharmaceutical composition are tablet, powder, granule, syrup,suspension, capsule and injection. Various carriers are used for theseformulations. For example, carriers for oral formulation includeexcipient, binder, lubricant, fluid promoter and coloring agent.

Parenteral formulation of the compound of the present invention such asinjection can be prepared generally by mixing, for example, withdistilled water for injection, physiological saline, glucose solution,vegetable oil for injection, propylene glycol and polyethylene glycol.In addition, in necessary, bactericide, antiseptics, stabilizer,tonicity agent and soothing agent can be added.

In case of administration of the compound of the present to humans, itcan be administered orally in the form of tablet, powder, granule,suppository, suspension and capsule. Parenteral administration can beperformed in the form of injection including drip infusion, cream orspray. Amount of administration depends on diseases, administrationform, age, body weight, and symptoms, but in general 3-1000 mg, 1-3times per day per adult are administered. Term for administration isgenerally from several days to 2 months, but the daily dose and dosageterm can be changed depending of symptom of patients.

EXAMPLES

Following examples illustrate the present invention in detail.

Thin layer chromatography (TLC) used is a precoated silica gel 60 F254(Merck). After developing with chloroform:methanol (100-4:1-0),acetonitrile:acetic acid:water (100-200:1-4:1-4), or ethylacetate:n-hexane (10-0:1-10), the product was confirmed by irradiationwith UV, or coloring reaction with ninhydrine or dinitrophenyl hydrazinehydrochloric acid solution. Column chromatography is used with silicagel (Wako gel C-200, Wako Pure Chemical Industry, Ltd.) and flushchromatography is used with silica gel 60 (230-400 mesh, Merck). Formeasurement with nuclear magnetic resonance (NMR), Gemini-300 (FT-NMR,Varian) is used. Deuterized chloroform (CDCl₃) is used, unlessspecified, as a solvent. Chemical shift is used with tetramethylsilane(TMS) as inner standard, and expressed by δ (ppm). Coupling constant isexpressed by J (Hz). Symbols of splitting patters are expressed by s;singlet, d; doublet, t; triplet, q; quartet, dd; doublet doublet, m;multiplet and br; broad, Mass spectrum (MS) used is JEOL-JMS-SX102(Nippon Denshi) and measured by fast atom bombardment mass spectrum(FAB-MS). Data are shown in table 1.

Example 1

3-(2-butoxy-1,1′-biphenyl-5-yl)propionic acid (Compound 01)

(Process d) Synthesis of Methyl3-(2-hydroxy-1,1′-biphenyl-5-yl)propionate (Intermediate 1)

3-(2-methoxy-1,1′-biphenyl-5-yl)propionic acid (4.00 g), which was aknown compound in the reference (R. R. Burtner et al. J. Am. Chem. Soc.75: 2334, 1953), was added to pyridine hydrochloric acid complexprepared by heating, after mixing pyridine with conc. Hydrochloric acid(each 15 ml), at 180° C. for 1 hour, and the mixture was stirred at 180°C. for 3 hours. Reaction mixture was poured into ice-cold 5 N—HCl (100ml) and extracted with ethyl acetate (150 ml×2). After drying theorganic layer, the solvent was distilled off in vacuo. Thionyl chloride(2.4 ml) was added dropwise to the residual methanol solution (75 ml)under ice cooling, and stirred for 16 hours by gradually changing toroom temperature. Solvent was concentrated in vacuo, and chloroform (200ml) was added to the residue, washed with aqueous saturated sodiumbicarbonate solution and aqueous saturated sodium chloride solution, inthis order, then the organic layer was dried and distilled of in vacuo.The residue was purified by flush column chromatography (hexane:ethylacetate=4:1) to obtain the compound of the title (3.97 g).

(Process c-1) Synthesis of Methyl3-(2-butoxy-1,1′-biphenyl-5-yl)propionate (Intermediate 2)

The intermediate 1 (1.20 g), n-butyl iodide (1.62 ml, Tokyo ChemicalInd. Co., Ltd.) and anhydride potassium carbonate (810 mg) were added toN,N-dimethylformamide (15.0 ml) and stirred at room temperature for 16hours. Ethyl acetate (200 ml) was added to the reaction mixture, whichwas washed with aqueous saturated sodium bicarbonate solution, aqueoussaturated ammonium chloride solution and aqueous saturated sodiumchloride solution, in this order, then the organic layer was dried anddistilled off in vacuo. The residue was purified by flush columnchromatography (hexane:ethyl acetate=8:1) to obtain the compound of thetitle (1.45 g).

(Process a) Synthesis of 3-(2-butoxy-1,1′-biphenyl-5-yl)propionic Acid(Compound 01)

Aqueous 2 N—NaOH solution (5.0 ml) was added to the methanol (10.0 ml)solution of the intermediate 2 (1.44 g) and stirred at room temperaturefor 16 hours. After concentrating the reaction mixture, the mixture wasacidified by adding 5% aqueous HCl, then extracted with ethyl acetate(200 ml). Organic layer was washed with saturated aqueous NaCl solution,dried and distilled off the solvent to obtain the compound of the title(1.29 g).

Rf=0.34 (chloroform:methanol=20:1).

Example 2

3-(2-isobutoxy-1,1′-biphenyl-5-yl)propionic Acid (Compound 02)

(Process c-1) Synthesis of Methyl3-(2-isobutoxy-1,1′-biphenyl-5-yl)propionate (Intermediate 3)

The compound of the title (420 mg) was obtained by reacting with theintermediate 1 (400 mg), isobutyl bromide (0.86 ml, Tokyo Chemical Ind.Co., Ltd.) and anhydrous potassium carbonate (270 mg) according to themethod described in the process c-1 in example 1. [Proviso that thefollowing modification was added. Reaction was carried out at 80° C. for24 hours. Purification was performed by flush column chromatography(hexane:ethyl acetate=7:1).]

(Process a) Synthesis of 3-(2-isobutoxy-1,1′-biphenyl-5-yl)propionicAcid (Compound 02)

The compound of the title (373 mg) was obtained by reacting with theintermediate 3 (410 mg) according to the process described in theprocess a in example 1. (Proviso that the reaction was performed at 65°C. for 2 hours.)

Rf=0.35 (chloroform:methanol=20:1)

Example 3

3-(2-pentyloxy-1,1′-biphenyl-5-yl)propionic Acid (Compound 03)

(Process c-1) Synthesis of Methyl3-(2-pentyloxy-1,1′-biphenyl-5-yl)propionate (Intermediate 4)

The compound of the title (509 mg) was obtained by reacting with theintermediate 1 (400 mg), n-pentyl iodide (0.61 ml, Tokyo Chemical Ind.Co., Ltd.) and anhydrous potassium carbonate (270 mg) according to themethod described in the process c-1 in example 1.

(Process a) Synthesis of 3-(2-pentyloxy-1,1′-biphenyl-5-yl)propionicAcid (Compound 03)

The compound of the title (461 mg) was obtained by reacting with theintermediate 4 (500 mg) according to the process described in theprocess a in example 1.

Rf=0.34 (chloroform:methanol=20:1)

Example 4

3-(2-cyclopentyloxy-1,1′-biphenyl-5-yl)propionic Acid (compound 04)

(Process c-2) Synthesis of Methyl3-(2-cylcopentyloxy-1,1′-biphenyl-5-yl)propionate (Intermediate 5)

The intermediate 1 (1.00 g), cyclopentyl alcohol (1.68 g, Tokyo ChemicalInd. Co., Ltd.) and triphenylphosphine (5.11 g, Kanto Chemical Co.) wereadded to anhydrous THF (20 ml) udner argon atmosphere at 0° C. andstirred. Diethyl azodicarboxylate (3.39 g, Nakaritesque Inc.) was slowlyadded dropwise and gradually changed to room temperature with stirringfor 1 day. Reaction mixture was diluted with ethyl acetate (100 ml), andwas washed with aqueous saturated ammonium chloride solution and dried,then the solvent was distilled off in vacuo. The residue was purified byflush column chromatography (hexane:ethyl acetate=9:1) to obtain thecompound of the title (820 mg).

(Process a) Synthesis of3-(2-cyclopentyloxy-1,1′-biphenyl-5-yl)propionic Acid (Compound 04)

The compound of the title (653 mg) was obtained by reacting with theintermediate 5 (820 mg) according to the process described in theprocess a in example 1.

Rf=0.35 (chloroform:methanol=20:1)

Example 5

3-(2-cyclohexyloxy-1,1′-biphenyl-5-yl)propionic Acid (Compound 05)

(Process c-2) Synthesis of Methyl3-(2-cyclohexyloxy-1,1′-biphenyl-5-yl)propionate (Intermediate 6)

The compound of the title (440 mg) was obtained by reacting with theintermediate 1 (1.03 g), cyclohexyl alcohol (2.02 g, Tokyo Chemical Ind.Co., Ltd.), triphenylphosphine (5.27 g) and diethyl azodicarboxylate(3.50 g) according to the method described in the process c-2 in example4.

(Process a) Synthesis of 3-(2-cyclohexyloxy-1,1′-biphenyl-5-yl)propionicAcid (Compound 05)

The compound of the title (288 mg) was obtained by reacting with theintermediate 6 (440 mg) according to the process described in theprocess a in example 1.

Rf=0.35 (chloroform:methanol=20:1)

Example 6

3-(2-cyclopentylmethyloxy-1,1′-biphenyl-5-yl)propionic Acid (Compound06)

(Process c-1) Synthesis of Methyl3-(2-cyclopentylmethyloxy-1,1′-biphenyl-5-yl)propionate (Intermediate 7)

The compound of the title (191 mg) was obtained by reacting with theintermediate 1 (256 mg), cyclopentylmethyl-p-toluenesulfonate [763 mg,prepared by reacting with cyclopenylcarbinol (Tokyo Chemical Ind. Co.,Ltd.) and p-toluenesulfonyl chlorid] and sodium hydride [60.0 mg, (60%abt. In oil) Tokyo Chemical Ind. Co., Ltd.], according to the methoddescribed in the process c-1 in example 1.

(Process a) Synthesis of3-(2-cyclopentylmethyloxy-1,1′-biphenyl-5-yl)propionic Acid (Compound06)

The compound of the title (182 mg) was obtained by reacting with theintermediate 7 (191 mg) according to the process described in theprocess 3 in example 1.

Rf=0.35 (chloroform:methanol=20:1)

Example 7

3-(2-cyclohexylmethyloxy-1,1′-biphenyl-5-yl)propionic Acid (Compound 07)

(Process c-1) Synthesis of Methyl3-(2-cyclohexylmethyloxy-1,1′-biphenyl-5-yl)propionate (Intermediate 8)

The compound of the title (642 mg) was obtained by reacting with theintermediate 1 (500 mg), bromomethyl cyclohexane (1.35 ml, TokyoChemical Ind. Co., Ltd.) and anhydrous potassium carbonate (337 mg)according to the method described in the process c-1 in example 1.[Proviso that the following modification was added. Reaction was carriedout at 80° C. for 24 hours. Purification was performed by flush columnchromatography (hexane:ethyl acetate=9:1).]

(Process a) Synthesis of3-(2-cyclohexylmethyloxy-1,1′-biphenyl-5-yl)propionic Acid (Compound 07)

The compound of the title (595 mg) was obtained by reacting with theintermediate 8 (630 mg) according to the process described in theprocess a in example 1. (Proviso that the reaction was performed at 65°C. for 6 hours.)

Rf=0.35 (chloroform:methanol=20:1)

Example 8

3-[2-(2-hydroxybutyloxy)-1,1′-biphenyl-5-yl]propionic acid (compound 08)

(Process c-3) Synthesis of Methyl3-[2-(2-hydroxybutyloxy)-1,1′-biphenyl-5-yl]propionate (Intermediate 9)

The intermediate 1 (600 mg), 1,2-butyleneoxide (1.00 ml, Tokyo ChemicalInd. Co., Ltd.) and triethylamine (1.60 ml) were added totetrahydrofuran (10 ml) and stirred in the autoclave at 170° C. for 3days. Reaction mixture was allowed to cool, concentrated in vacuo andadded ethyl acetate (200 ml), then washed with saturated aqueousammonium chloride solution, saturated aqueous sodium bicarbonatesolution and saturated aqueous sodium chloride solution, in this order.After drying the organic layer, the solvent was distilled off in vacuo.The residue was purified by using silica gel column chromatography(hexane:ethyl acetate=5:1) to obtain the compound in the title (516 mg).

(Process a) Synthesis of3-[2-(2-hydroxybutyloxy)-1,1′-biphenyl-5-yl]propionic Acid (Compound 08)

The compound of the title (454 mg) was obtained by reacting with theintermediate 9 (505 mg) according to the process described in theprocess a in example 1. (Proviso that the reaction was performed at 65°C. for 3 hours.)

Rf=0.47 (chloroform:methanol=10:1)

Example 9

Optically Active 3-[2-(2-hydroxybutyloxy)-1,1′-biphenyl-5-yl]propionicAcid (Compound 09)

(Process p) Preparative HPLC of Optically Active Methyl3-[2-(2-hydroxybutyloxy)-1,1′-biphenyl-5-yl]propionate (Intermediate 10)

The compound in the title (184 mg) was obtained by treating withpreparative HPLC using a column CHIRALCEL OD (2 cm×25 cm, Daicel Chem.Ind. Ltd.), in which solution prepared by dissolving the intermediate 9(500 mg) in ethanol at 10 mg/ml was used each 100 μl for treatment.Optical purity: 97.2% ee.

Condition of preparative HPLC: Column temp. 35° C., monitored by UVabsorption at 254 nm, solvent; hexane:ethanol=3.8:0.2, flow rate: 4.0ml/min., retention time 15.9 min.

(Process a) Synthesis of Optically Active3-[2-(2-hydroxybutyloxy)-1,1′-biphenyl-5-yl]propionic Acid (Compound 09)

The compound of the title (139 mg) was obtained by reacting with theintermediate 10 (184 mg) according to the process described in theprocess a in example 1.

Condition of preparative HPLC: CHIRALCEL AD (0.46 cm×25 cm, Daicel Chem.Ind. Ltd.), column temp. 35° C., monitored by UV absorption at 254 nm,solvent; hexane:ethanol:trifluoroacetic acid=85:15:0.1, flow rate: 0.5ml/min., retention time 13.6 min. Optical purity: 96.1% ee.

Rf=0.47 (chloroform:methanol=10:1)

Example 10

Optically Active 3-[2-(2-hydroxybutyloxy)-1,1′-biphenyl-5-yl]propionicAcid (Compound 10)

(Process p) Preparative HPLC of Optically Active Methyl3-[2-(2-hydroxybutyloxy)-1,1′-biphenyl-5-yl]propionate (Intermediate 11)

The compound in the title (201 mg) was obtained from the intermediate 9(500 mg) according to the procedure described in the process p inexample 9. Optical purity: 93.9% ee.

Condition of preparative HPLC: Column temp. 35° C., solvent;hexane:ethanol=3.8:0.2, flow rate: 4.0 ml/min., retention time 17.8 min.

(Process a) Synthesis of Optically Active3-[2-(2-hydroxybutyloxy)-1,1′-biphenyl-5-yl]propionic Acid (Compound 10)

The compound of the title (183 mg) was obtained by reacting with theintermediate 11 (201 mg) according to the process described in theprocess a in example 1.

Condition of preparative HPLC: CHIRALCEL AD (0.46 cm×25 cm), columntemp. 35° C., monitored by UV absorption at 254 nm, solvent;hexane:ethanol:trifluoroacetic acid 85:15:0.1, flow rate: 0.5 ml/min.,retention time 14.7 min. Optical purity: 94.4% ee.

Rf=0.47 (chloroform:methanol 10:1)

Example 11

3-[2-(2-oxobutyloxy)-1,1′-biphenyl-5-yl]propionic Acid (Compound 11)

(Process c-1) Synthesis of Methyl3-[2-(2-oxobutyloxy-1,1′-biphenyl-5-yl)propionate (Intermediate 12)

The compound of the title (1.30 g) was obtained by reacting with theintermediate 1 (1.02 g), 1-bromo-2-butanone (1.81 g, Aldrich Inc.) andanhydrous potassium carbonate (1.66 g) according to the method describedin the process c-1 in example 1. [Proviso that the followingmodification was added. Reaction was carried out at room temperature for3 hours. Purification was performed by flush column chromatography(hexane:ethyl acetate=5:1).]

(Process a) Synthesis of3-[2-(2-oxobutyloxy)-1,1′-biphenyl-5-yl]propionic Acid (Compound 11)

The compound of the title (198 mg) was obtained by reacting with theintermediate 12 (326 mg) according to the process described in theprocess a in example 1.

Rf=0.52 (chloroform:methanol=10:1)

Example 12

3-(2-carboxymethyloxy-1,1′-biphenyl-5-yl)propionic acid (Compound 12)

(Process c-1) Synthesis of Methyl 3-(2-ethoxycarbonylmethyloxy-1,1′-biphenyl-5-yl)propionate (Intermediate 13)

The compound of the title (529 mg) was obtained by reacting with theintermediate 1 (400 mg), ethyl bromoacetate (0.52 ml, Tokyo ChemicalInd. Co., Ltd.) and anhydrous potassium carbonate (270 mg) according tothe method described in the process c-1 in example 1. [Proviso thatpurification was performed by flush column chromatography (hexane:ethylacetate=5:1).]

(Process a) Synthesis of3-(2-carboxymethyloxy-1,1′-biphenyl-5-yl)propionic Acid (Compound 12)

The compound of the title (433 mg) was obtained by reacting with theintermediate 13 (505 mg) according to the process described in theprocess a in example 1.

Rf=0.47 (acetonitrile:acetic acid:water 100:2:1)

Example 13

3-(2-carbamoylmethyloxy-1,1′-biphenyl-5-yl)propionic Acid (Compound 13)

(Process c-1) Synthesis of Methyl3-(2-carbamoylmethyloxy-1,1′-biphenyl-5-yl)propionate (Intermediate 14)

The compound of the title (433 mg) was obtained by reacting with theintermediate 1 (391 mg), 2-bromoacetamide (414 mg, Aldrich Inc.) andanhydrous potassium carbonate (415 mg) according to the method describedin the process c-1 in example 1. [Proviso that purification wasperformed by flush column chromatography (chloroform:methanol=95:5).]

(Process a) Synthesis of3-(2-carbamoylmethyloxy-1,1′-biphenyl-5-yl)propionic Acid (Compound 13)

The compound of the title (127 mg) was obtained by reacting with theintermediate 14 (319 mg) in a mixture of purified water (10 ml) andtetrahydrofuran (10 ml) with triethylamine (1.0 ml) according to theprocess described in the process a in example 1. (Proviso that thereaction was proceeded at room temperature for 10 days.)

Rf=0.35 (chloroform:methanol=10:1)

Example 14

3-(2-butoxy-3-nitro-1,1′-biphenyl-5-yl)propionic Acid (Compound 14)

(Process n) Synthesis of Methyl3-(2-butoxy-3-nitro-1,1′-biphenyl-5-yl)propionate (Intermediate 15)

Previously prepared mixture of 98% fuming nitric acid (0.81 ml, d=1.52,Wako Pure Chemical Ind., Ltd.) and acetic anhydride (4.0 ml) was addeddropwise to the acetic anhydride (10 ml) solution of the intermediate 2(1.20 g) at −10° C. for 5 minutes. The reaction mixture was stirred at−10° C. for 15 minutes. Then the reaction mixture was poured into theice-water (50 ml), neutralized with 5% aqueous sodium hydroxidesolution, and extracted with isopropyl ether (150 ml×2). The organiclayer was washed with saturated aqueous sodium bicarbonate solution,saturated aqueous ammonium chloride solution and saturated aqueoussodium chloride solution, in this order. The organic layer was dried andthe solvent was distilled off in vacuo. The residue was purified byusing flush column chromatography (hexane:ethyl acetate=7:1) to obtainthe compound in the title (647 mg).

(Process a) Synthesis of3-(2-butoxy-3-nitro-1,1′-biphenyl-5-yl)propionic Acid (Compound 14)

The compound of the title (244 mg) was obtained by reacting with theintermediate 14 (275 mg) according to the process described in theprocess a in example 1.

Rf=0.61 (chloroform:methanol=10:1)

Example 15

3-(3-acetylamino-2-butoxy-1,1′-biphenyl-5-yl)propionic Acid (Compound15)

(Process m) Synthesis of Methyl3-(3-amino-2-butoxy-1,1′-biphenyl-5-yl)propionate (Intermediate 16)

Iron powder (395 mg, Kanto Chemical Co.) and conc. HCl (0.90 ml) wereadded to methanol (10 ml) solution of the intermediate 15 (375 mg), andstirred at room temperature for 3 hours. Insoluble materials wereremoved by filtration using Celite. Ethyl acetate (200 ml) was added tothe filtrate, washed with saturated aqueous sodium bicarbonate solution,saturated aqueous ammonium chloride solution and saturated aqueoussodium chloride solution, in this order. The organic layer was dried andthe solvent was distilled off in vacuo. The residue was purified byusing flush column chromatography (hexane:ethyl acetate=3:1) to obtainthe compound in the title (350 mg).

(Process a) Synthesis of3-(3-acetylamino-2-butoxy-1,1′-biphenyl-5-yl)propionic Acid (Compound15)

The compound of the title (323 mg) was obtained by reacting with theintermediate 17 (345 mg) according to the process described in theprocess a in example 1.

Rf=0.54 (chloroform:methanol=10:1)

Example 16

3-(2-butoxy-3-methylsulfonylamino-1,1′-biphenyl-5-yl)propionic Acid(Compound 16)

(Process 1-1) Synthesis of Methyl3-(2-butoxy-3-methylsulfonylamino-1,1′-biphenyl-5-yl)propionate(Intermediate 18)

The compound of the title (513 mg) was obtained by reacting with theintermediate 16 (435 mg) and methylsulfonyl chloride (0.16 ml, Wako PureChemical Ind., Ltd.) in pyridine (5.0 ml) according to the methoddescribed in the process 1-1 in example 15. (Proviso that reaction wasperformed under ice cooling for 1 hour and at room temperature for 1hour.)

(Process a) Synthesis of3-(2-butoxy-3-methylsulfonylamino-1,1′-biphenyl-5-yl)propionic Acid(Compound 16)

The compound of the title (422 mg) was obtained by reacting with theintermediate 18 (465 mg) according to the process described in theprocess a in example 1.

Rf=0.54 (chloroform:methanol=10:1)

Example 17

3-(3-acetylamino-2-cyclohexylmethyloxy-1,1′-biphenyl-5-yl)propionic Acid(Compound 17)

(Process n) Synthesis of Methyl3-(2-cyclohexylmethyloxy-3-nitro-1,1′-biphenyl-5-yl)propionate(Intermediate 19)

The compound of the title (892 mg) was obtained by reacting with theintermediate 8 (1.00 g) according to the method described in the processn in example 14.

(Process m) Synthesis of Methyl3-(3-amino-2-cyclohexylmethyloxy-1,1′-biphenyl-5-yl)propionate(Intermediate 20)

The compound of the title (799 mg) was obtained by reacting with theintermediate 19 (870 mg) according to the process described in theprocess m in example 15.

(Process 1-1) Synthesis of Methyl3-(3-acetylamino-2-cyclohexylmethyloxy-1,1′-biphenyl-5-yl)propionate(Intermediate 21)

The compound of the title (383 mg) was obtained by reacting with theintermediate 20 (390 mg) and acetic anhydride (0.30 ml) according to theprocess described in the process 1-1 in example 15.

(Process a) Synthesis of3-(3-acetylamino-2-cyclohexylmethyloxy-1,1-biphenyl-5-yl)propionic Acid(Compound 17)

The compound of the title (347 mg) was obtained by reacting with theintermediate 21 (375 mg) according to the process described in theprocess a in example 1.

Rf=0.44 (chloroform:methanol=10:1)

Example 18

3-(2-cyclohexylmethoxy-3-methylsulfonylamino-1,1′-biphenyl-5-yl)propionicAcid (Compound 18)

(Process 1-1) Synthesis of Methyl3-(2-cyclohexylmethyloxy-3-methylsulfonylamino-1,1′-biphenyl-5-yl)propionate(Intermediate 22)

The compound of the title (403 mg) was obtained by reacting with theintermediate 20 (390 mg) and methylsulfonyl chloride (0.13 ml) inpyridine (3.0 ml) according to the method described in the process 1-1in example 15. (Proviso that reaction was performed under ice coolingfor 0.5 hour and at room temperature for 0.5 hour.)

(Process a) Synthesis of3-(2-cyclohexylmethyloxy-3-methylsulfonylamino-1,1′-biphenyl-5-yl)propionicAcid (Compound 18)

The compound of the title (364 mg) was obtained by reacting with theintermediate 22 (395 mg) according to the process described in theprocess a in example 1.

Rf=0.48 (chloroform:methanol=10:1)

Example 19

3-(2-cyclohexylmethyloxy-3-hydroxyacetylamino-1,1′-biphenyl-5-yl)propionicAcid (Compound 19)

(Process 1-1) Synthesis of Methyl3-(3-acetoxyacetylamino-2-cyclohexylmethyloxy-1,1′-biphenyl-5-yl)propionate(Intermediate 23)

The compound of the title (480 mg) was obtained by reacting with theintermediate 20 (415 mg), acetoxyacetyl chloride (0.15 ml, Aldrich Inc.)and pyridine (0.10 ml) according to the method described in the process1-1 in example 15. (Proviso that reaction was performed under icecooling for 0.5 hour and at room temperature for 1 hour.)

(Process a) Synthesis of3-(2-cyclohexylmethyloxy-3-hydroxyacetylamino-1,1′-biphenyl-5-yl)propionicAcid (Compound 19)

The compound of the title (394 mg) was obtained by reacting with theintermediate 23 (470 mg) according to the process described in theprocess a in example 1.

Rf=0.26 (chloroform:methanol=10:1)

Example 20

3-(2-cyclohexylmethyloxy-3-(N,N-dimethylcarbamoyl)amino-1,1′-biphenyl-5-yl)propionicAcid (Compound 20)

(Process 1-1) Synthesis of Methyl3-[2-cyclohexylmethyloxy-3-(N,N-dimethylcarbamoyl)amino-1,1′-biphenyl-5-yl)propionate(Intermediate 24)

The compound of the title (278 mg) was obtained by reacting with theintermediate 20 (410 mg) and dimethylcarbamoyl chloride (0.62 ml, TokyoChemical Ind. Co., Ltd.) in pyridine (5.0 ml) according to the methoddescribed in the process 1-1 in example 15. (Proviso that reaction wasperformed under ice cooling for 0.5 hour and at room temperature for 48hours.)

(Process a) Synthesis of3-[2-cyclohexylmethyloxy-3-(N,N-dimethylcarbamoyl)amino-1,1′-biphenyl-5-yl)propionicAcid (Compound 20)

The compound of the title (231 mg) was obtained by reacting with theintermediate 24 (270 mg) according to the process described in theprocess a in example 1.

Rf=0.40 (chloroform:methanol=10:1)

Example 21

3-[2-cyclohexylmethyloxy-3-(N,N-dimethylsulfamoyl)amino-1,1′-biphenyl-5-yl)propionicAcid (Compound 21)

(Process 1-1) Synthesis of Methyl3-[2-cyclohexylmethyloxy-3-(N,N-dimethylsulfamoyl)amino-1,1′-biphenyl-5-yl)propionate(Intermediate 25)

The compound of the title (290 mg) was obtained by reacting with theintermediate 20 (410 mg), dimethylsulfamoyl chloride (0.48 ml, AldrichInc.) and N,N-dimethylaminopyridine (275 mg, Tokyo Chemical Ind. Co.,Ltd.) according to the method described in the process 1-1 in example15. (Proviso that reaction was performed under ice cooling for 0.5 hourand at room temperature for 48 hours.)

(Process a) Synthesis of3-[2-cyclohexylmethyloxy-3-(N,N-dimethylsulfamoyl)amino-1,1′-biphenyl-5-yl)propionicAcid (Compound 21)

The compound of the title (248 mg) was obtained by reacting with theintermediate 25 (280 mg) according to the process described in theprocess a in example 1.

Rf=0.42 (chloroform:methanol=10:1)

Example 22

3-(3-carbamoylamino-2-cyclohexylmethyloxy-1,1′-biphenyl-5-yl)propionicAcid (Compound 22)

(Process 1-2) Synthesis of Methyl3-(3-carbamoylamino-2-cyclohexylmethyloxy-1,1′-biphenyl-5-yl)propionate(Intermediate 26)

Potassium cyanate (180 mg, Wako Pure Chemical Ind., Ltd.) was added tothe solution of the intermediate 20 (410 mg) in a mixture of acetic acid(5 ml) and purified water (1 ml) and stirred at room temperature for 1hour. The reaction mixture was poured into the ice-water (50 ml) andextracted with isopropyl ether (150 ml×2). The organic layer was washedwith saturated aqueous sodium bicarbonate solution, saturated aqueousammonium chloride solution and saturated aqueous sodium chloridesolution, in this order. The organic layer was dried and the solvent wasdistilled off in vacuo to obtain the compound in the title (367 mg).

(Process a) Synthesis of3-(3-carbamoylamino-2-cyclohexylmethyloxy-1,1′-biphenyl-5-yl)propionicAcid (Compound 22)

The compound of the title (293 mg) was obtained by reacting with theintermediate 26 (350 mg) according to the process described in theprocess a in example 1.

Rf=0.37 (acetonitrile:acetic acid:water=100:2:1)

Example 23

3-(2-cyclohexylmethyloxy-3-methoxy-1,1′-biphenyl-5-yl)propionic Acid(Compound 23)

(Process c-1) Synthesis of4-cyclohexylmethyloxy-3-iodo-5-methoxybenzaldehyde (Intermediate 27)

The compound in the title (749 mg) was obtained by reacting with5-iodovanillin (556 mg, Aldrich Inc.), bromomethyl cyclohexane (1.77 g)and potassium carbonate anhydride (1.38 g) according to a processdescribed in the process c-1 in example 1.

(Process i) Synthesis of4-cyclohexylmethyloxy-5-methoxy-3-phenylbenzaldehyde (Intermediate 28)

The intermediate 27 (749 mg), phenyl boric acid (1.22 g, Tokyo ChemicalInd. Co., Ltd.), potassium carbonate (1.38 g) and tetrakis(triphenylphosphine)palladium (0)(462 mg, Tokyo Chemical Ind. Co., Ltd.)were added to toluene (5 ml) and stirred at 100° C. for 12 hours underargon atmosphere. The reaction mixture was cooled and water (50 ml) wasadded thereto, then extracted with ethyl acetate (50 ml×3). The organiclayer was washed with saturated aqueous ammonium chloride solution andsaturated aqueous sodium chloride solution in this order, and dried. Thesolvent was removed off in vacuo and the residue was purified usingflush column chromatography (hexane:ethyl acetate=9 1) to obtain thecompound in the title (650 mg).

(Process h) Synthesis of Ethyl3-(2-cyclohexylmethyloxy-3-methoxy-1,1′-biphenyl-5-yl)acrylate(Intermediate 29)

Ethyl diethylphosphono acetate (896 mg, Tokyo Chemical Ind. Co., Ltd.)and sodium hydride (160 mg) were added to 1,2-dimethoxyethane (10 ml) at0° C. under argon atmosphere and stirred. Intermediate 28 (650 mg) wasadded, when hydrogen gas generation was stopped, and stirred at roomtemperature for 1 hour. The reaction mixture was washed with saturatedaqueous ammonium chloride solution, dried and distilled off the solventin vacuo. The residue was purified with flush column chromatography(hexane:ethyl acetate=9:1) to obtain the compound in the title (785 mg).

(Process g) Synthesis of Ethyl3-(2-cyclohexylmethyloxy-3-methoxy-1,1′-biphenyl-5-yl)propionate(Intermediate 30)

The intermediate 29 (785 mg) and 10% palladium carbon powder (50 mg,Merck) were added to ethanol (5 ml), and stirred at room temperature for3 hours under hydrogen atmosphere. The reaction mixture was filtered andthe solvent was removed off in vacuo to obtain the compound in the title(753 mg).

(Process a) Synthesis of3-(2-cyclohexylmethyloxy-3-methoxy-1,1′-biphenyl-5-yl)propionic Acid(Compound 23)

The compound of the title (668 mg) was obtained by reacting with theintermediate 30 (753 mg) according to the process described in theprocess a in example 1.

Rf=0.53 (chloroform:methanol=10:1)

Example 24

3-(2-cyclohexylmethyloxy-3-hydroxy-1,1′-biphenyl-5-yl)propionic Acid(Compound 24)

(Process c-2) Synthesis of Methyl3-(2-cyclohexylmethyloxy-3-hydroxy-1,1′-biphenyl-5-yl)propionate(Intermediate 31)

The compound of the title (334 mg) was obtained by reacting with thecompound 23 (334 mg), pyridine (7 ml), conc. HCl (7 ml) and thionylchloride (238 mg) according to the method described in the process d inexample 1.

(Process a) Synthesis of3-(2-cyclohexylmethyloxy-3-hydroxy-1,1′-biphenyl-5-yl)propionic Acid(Compound 24)

The compound of the title (120 mg) was obtained by reacting with theintermediate 31 (151 mg) according to the process described in theprocess a in example 1.

Rf=0.38 (chloroform:methanol=10:1)

Example 25

3-(2-cyclohexylmethyloxy-4′-hydroxy-1,1′-biphenyl-5-yl)propionic Acid(Compound 25)

(Process c-1) Synthesis of 3-bromo-4-cyclohexylmethyloxy Benzaldehyde(Intermediate 32)

The compound in the title (1.97 g) was obtained by reacting with3-bromo-4-hydroxybenzaldehyde [1.51 g, prepared from3-bromo-p-anisaldehyde (Aldrich Inc.) using pyridine hydrochloric acidcomplex described in the process d in example 1], bromomethylcyclohexane (3.34 g) and anhydride potassium carbonate (2.61 g)according to a process described in the process c-1 in example 1.

(Process i) Synthesis of 3-(4′-benzyloxyphenyl)-4-cyclohexylmethyloxyBenzaldehyde (Intermediate 33)

The intermediate 32 (1.76 g), 4-benzyloxyphenyl boric acid [6.75 g,4-benzyloxy bromobenzene was prepared according to a process describedin the process c-1 in example 1 from 4-bromophenol (Tokyo Chemical Ind.Co., Ltd.) and benzyl chloride (Tokyo Chemical Ind. Co., Ltd.), and theproduct was prepared according to a method described in the reference YSatoh et al. SYNTHESIS page 1146, 1994], anhydrous potassium carbonate(4.09 g) and tetrakis (triphenylphosphine)palladium (0)(342 mg) werereacted according to the method described in the process i in example 23to obtain the compound in the title (2.30 g).

(Process h) Synthesis of Methyl3-(4′-benzyloxy-2-cyclohexylmethyloxy-1,1′-biphenyl-5-yl)acrylate(Intermediate 34)

The intermediate 33 (2.30 g), ethyl diethylphosphono acetate (1.99 g)and 28% methanol solution of sodium methoxide (1.75 ml, Wako PureChemical Ind., Ltd.) were reacted according to the process described inthe process h in example 23 to obtain the compound in the title (1.45g).

(Process g) Synthesis of Methyl3-(2-cyclohexylmethyloxy-4′-hydroxy-1,1′-biphenyl-5-yl)propionate(Intermediate 35)

The intermediate 34 (1.45 g) and 10% palladium carbon powder (300 mg)were reacted under hydrogen atmosphere according to the method describedin the process g in example 23 to obtain the compound in the title (1.13g). Proviso that methanol was used as the solvent.

(Process a) Synthesis of3-(2-cyclohexylmethyloxy-4′-hydroxy-1,1′-biphenyl-5-yl)propionic Acid(Compound 25)

The compound of the title (1.09 g) was obtained by reacting with theintermediate 35 (1.13 g) according to the process described in theprocess a in example 1.

Rf=0.36 (chloroform:methanol=10:1)

Example 26

3-(2-cyclohexylmethyloxy-4′-methoxy-1,1′-biphenyl-5-yl)propionic Acid(Compound 26)

(Process i) Synthesis of 3-(4′-methoxyphenyl)-4-cyclohexylmethyloxyBenzaldehyde (Intermediate 36)

The intermediate 32 (2.00 g), 4-methoxyphenyl boric acid (500 mg,Aldrich Inc.), potassium carbonate anhydride (464 mg) and tetrakis(triphenylphosphine)palladium (0)(39 mg) were reacted according to themethod described in the process i in example 23 to obtain the compoundin the title (218 mg).

(Process h) Synthesis of Methyl3-(2-cyclohexylmethyloxy-4′-methoxy-1,1′-biphenyl-5-yl)acrylate(Intermediate 37)

The intermediate 36 (218 mg), ethyl diethylphosphono acetate (226 mg)and 28% methanol solution of sodium methoxide (0.21 ml) were reactedaccording to the process described in the process h in example 23 toobtain the compound in the title (245 mg). Proviso that methanol wasused as the solvent.

(Process g) Synthesis of Methyl3-(2-cyclohexylmethyloxy-4′-methoxy-1,1′-biphenyl-5-yl)propionate(Intermediate 38)

The intermediate 38 (245 mg), ammonium formate (163 mg, Wako PureChemical Ind., Ltd.) and 10% palladium carbon powder (25 mg) werereacted under according to the method described in the process g inexample 23 to obtain the compound in the title (238 mg).

(Process a) Synthesis of3-(2-cyclohexylmethyloxy-4′-methoxy-1,1′-biphenyl-5-yl)propionic Acid(Compound 26)

The compound of the title (229 mg) was obtained by reacting with theintermediate 38 (238 mg) according to the process described in theprocess a in example 1.

Rf=0.56 (chloroform:methanol=10:1)

Example 27

3-(2-cyclohexylmethyloxy-1,1-biphenyl-5-yl)propionamide (Compound 27)

(Process b-1) Synthesis of3-(2-cyclohexylmethyloxy-1,1-biphenyl-5-yl)propionamide (Compound 27)

N,N-dimethylformamide (one drop) and thionyl chloride (0.35 ml) wereadded to toluene (4 ml) solution of the compound 7 (400 mg) and refluxedfor 1 hour. After the reaction mixture was concentrated in vacuo,toluene (2 ml) was added and subjected to azeotropic drying in vacuo(twice). Residual tetrahydrofuran (2 ml) was added dropwise to 25%aqueous ammonia (5.0 ml) under ice-cooling, and stirred for 1 hour.Ethyl acetate (200 ml) was added to the reaction mixture. The reactionmixture was washed with saturated aqueous sodium bicarbonate solution,saturated aqueous ammonium chloride solution and saturated aqueoussodium chloride solution, in this order. The organic layer was dried andthe solvent was distilled off in vacuo to obtain the compound in thetitle (391 mg).

Rf=0.36 (chloroform:methanol=10:1)

Example 28

4-(2-butoxy-1,1′-biphenyl-5-yl)butyric Acid (Compound 28)

(Process f) Synthesis of Methyl 4-(2-methoxy-1,1′-biphenyl-5-yl)-4-oxoButyrate (Intermediate 39)

A solution of aluminum chloride (2.68 g, purity 99.99%, Aldrich Inc.)suspended in methylene chloride (50 ml) was stirred at 0° C. Methylenechloride (5 ml) solution of 3-carbomethoxypropionyl chloride (3.01 g,Aldrich Inc.) was added thereto and stirred at 0° C. for 10 minutes.Methylene chloride (20 ml) solution of 2-methoxybiphenyl (2.00 g,Aldrich Inc.) was added dropwise for 20 minutes and stirred at 0° C for30 minutes and later at room temperature for 3 hours. Reaction mixturewas poured into ice-cold 3 N—HCl (150 ml), vigorously stirred andextracted with methylene chloride (50 ml×3). The organic layer waswashed with water, aqueous saturated sodium bicarbonate solution, waterand aqueous saturated sodium chloride solution, in this order, then theorganic layer was dried and distilled of in vacuo to obtain the compoundin the title (2.81 g).

(Process e) Synthesis of Methyl 4-(2-methoxy-1,1′-biphenyl-5-yl)butyrate(Intermediate 40)

The intermediate 39 (2.02 g), conc. HCl (4 drops) and 10% palladiumcarbon powder (1.01 g) were added to a mixture of methylene chloride andmethanol (1:2) (30 ml) and stirred at room temperature for overnightunder hydrogen atmosphere. The reaction mixture was filtered and thesolvent was distilled off. The residue was purified by flush columnchromatography (hexane:ethyl acetate=12:1) to obtain the compound in thetitle (1.82 g).

(Process c-2) Synthesis of Methyl4-(2-hydroxy-1,1′-biphenyl-5-yl)butyrate (Intermediate 41)

The compound in the title (389 mg) was obtained by reacting with theintermediate 40 (603 mg), pyridine (10 ml), conc. HCl (10 ml), methanol(5 ml) and thionyl chloride (505 mg) according to the method describedin the process d in example 1.

(Process c-1) Synthesis of Methyl4-(2-butoxy-1,1′-biphenyl-5-yl)butyrate (Intermediate 42)

The intermediate 41 (300 mg), butane iodide (404 mg) and anhydridepotassium carbonate (277 mg) were reacted according to the processdescribed in the process c-1 in example 1 to obtain the compound of thetitle (344 mg).

(Process a) Synthesis of 4-(2-butoxy-1,1′-biphenyl-5-yl)butyric Acid(Compound 28)

The compound of the title (175 mg) was obtained by reacting theintermediate 42 (285 mg) according to the process described in theprocess a in example 1.

Rf=0.38 (chloroform:methanol=20:1).

Example 29

4-(2-isobutoxy-1,1′-biphenyl-5-yl)butyric Acid (Compound 29)

(Process c-1) Synthesis of Methyl4-(2-isobutoxy-1,1′-biphenyl-5-yl)butyrate (Intermediate 43)

The compound of the title (585 mg) was obtained by reacting with theintermediate 41(540 mg), isobutyl bromide (1.37 g) and anhydrouspotassium carbonate (1.38 g) according to the method described in theprocess c-1 in example 1.

(Process a) Synthesis of 4-(2-isobutoxy-1,1′-biphenyl-5-yl)butyric Acid(Compound 29)

The compound of the title (561 mg) was obtained by reacting with theintermediate 43 (585 mg) according to the process described in theprocess a in example 1.

Rf=0.38 (chloroform:methanol=20:1)

Example 30

4-[2-(1-methylpropyloxy)-1,1′-biphenyl-5-yl]butyric Acid (Compound 30)

(Process c-1) Synthesis of Methyl4-[2-(1-methylpropyloxy)-1,1′-biphenyl-5-yl)butyrate (Intermediate 44)

The compound of the title (140 mg) was obtained by reacting with theintermediate 41 (250 mg), 2-iodo butane (1.84 g, Tokyo Chemical Ind.Co., Ltd.) and anhydrous potassium carbonate (690 mg) according to themethod described in the process c-1 in example 1.

(Process a) Synthesis of4-[2-(1-methylpropyloxy)-1,1′-biphenyl-5-yl)butyric Acid (Compound 30)

The compound of the title (123 mg) was obtained by reacting with theintermediate 44 (140 mg) according to the process described in theprocess a in example 1.

Rf=0.37 (chloroform:methanol=20:1)

Example 31

4-(2-pentyloxy-1,1′-biphenyl-5-yl)butyric Acid (Compound 31)

(Process c-1) Synthesis of Methyl4-(2-pentyloxy-1,1′-biphenyl-5-yl)butyrate (Intermediate 45)

The compound of the title (340 mg) was obtained by reacting with theintermediate 41 (270 mg), iodo pentane (910 mg) and potassium carbonateanhydride (680 mg) according to the method described in the process c-1in example 1.

(Process a) Synthesis of 4-(2-pentyloxy-1,1′-biphenyl-5-yl)butyric Acid(Compound 31)

The compound of the title (251 mg) was obtained by reacting with theintermediate 45 (340 mg) according to the process described in theprocess a in example 1.

Rf=0.38 (chloroform:methanol=20:1)

Example 32

4-[2-(1-methylbutyloxy)-1,1′-biphenyl-5-yl]butyric Acid (Compound 32)

(Process c-1) Synthesis of Methyl4-[2-(1-methylbutyloxy)-1,1′-biphenyl-5-yl]butyrate (Intermediate 46)

The compound of the title (464 mg) was obtained by reacting with theintermediate 41 (540 mg), 2-bromo pentane (1.51 g, Tokyo Chemical Ind.Co., Ltd.) and potassium carbonate anhydride (1.38 g) according to themethod described in the process c-1 in example 1.

(Process a) Synthesis of4-[2-(1-methylbutyloxy)-1,1′-biphenyl-5-yl]butyric Acid (Compound 32)

The compound of the title (434 mg) was obtained by reacting with theintermediate 48 (454 mg) according to the process described in theprocess a in example 1.

Rf=0.38 (chloroform:methanol=20:1)

Example 33

4-[2-(2-methylbutoxy)-1,1′-biphenyl-5-yl]butyric Acid (Compound 33)

(Process c-1) Synthesis of Methyl4-[2-(2-methylbutoxy)-1,1′-biphenyl-5-yl]butyrate (Intermediate 47)

The compound of the title (495 mg) was obtained by reacting with theintermediate 41 (503 mg), sodium hydride (75.0 mg) and2-methyl-1-(p-toluenesulfonyl)butane [528 mg, prepared from2-methyl-1-butanol (Tokyo Chemical Ind. Co., Ltd.) and p-toluenesulfonylchloride in pyridine] according to the method described in the processc-1 in example 1.

(Process a) Synthesis of4-[2-(2-methylbutoxy)-1,1′-biphenyl-5-yl]butyric Acid (Compound 33)

The compound of the title (455 mg) was obtained by reacting with theintermediate 47 (495 mg) according to the process described in theprocess a in example 1.

Rf=0.36 (chloroform:methanol=20:1)

Example 34

4-(2-isopentyloxy-1,1′-biphenyl-5-yl)butyric Acid (Compound 34)

(Process c-1) Synthesis of Methyl4-(2-isopentyloxy-1,1′-biphenyl-5-yl)butyrate (Intermediate 48)

The compound of the title (680 mg) was obtained by reacting with theintermediate 41(540 mg), 1-bromo-3-methylbutane (1.51 g, Tokyo ChemicalInd. Co., Ltd.) and potassium carbonate anhydride (1.38 g) according tothe method described in the process c-1 in example 1.

(Process a) Synthesis of 4-(2-isopentyloxy-1,1′-biphenyl-5-yl)butyricAcid (Compound 34)

The compound of the title (642 mg) was obtained by reacting with theintermediate 48 (670 mg) according to the process described in theprocess a in example 1.

Rf=0.35 (chloroform:methanol=20:1)

Example 35

4-(2-cyclopentyloxy-1,1′-biphenyl-5-yl)butyric Acid (Compound 35)

(Process c-2) Synthesis of Methyl4-(2-cyclopentyloxy-1,1′-biphenyl-5-yl)butyrate (Intermediate 49)

The compound of the title (900 mg) was obtained by reacting with theintermediate 41 (1.00 g), cyclopentyl alcohol (1.59 g),triphenylphosphine (4.85 g) and diethyl azodicarboxylate (3.22 g)according to the method described in the process c-2 in example 4.

(Process a) Synthesis of 4-(2-cyclopentyloxy-1,1′-biphenyl-5-yl)butyricAcid (Compound 35)

The compound of the title (781 mg) was obtained by reacting with theintermediate 49 (900 mg) according to the process described in theprocess a in example 1.

Rf=0.37 (chloroform:methanol=20:1)

Example 36

4-(2-cyclohexyloxy-1,1′-biphenyl-5-yl)butyric Acid (Compound 36)

(Process c-2) Synthesis of Methyl4-(2-cyclohexyloxy-1,1′-biphenyl-5-yl)butyrate (Intermediate 50)

The compound of the title (630 mg) was obtained by reacting with theintermediate 41 (1.04 g), cyclohexyl alcohol (1.92 g),triphenylphosphine (5.05 g) and diethyl azodicarboxylate (3.35 g)according to the method described in the process c-2 in example 4.

(Process a) Synthesis of 4-(2-cyclohexyloxy-1,1′-biphenyl-5-yl)butyricAcid (Compound 36)

The compound of the title (514 mg) was obtained by reacting with theintermediate 50 (630 mg) according to the process described in theprocess a in example 1.

Rf=0.38 (chloroform:methanol=20:1)

Example 37

4-(2-cyclopentylmethyloxy-1,1′-biphenyl-5-yl)butyric Acid (Compound 37)

(Process c-1) Synthesis of Methyl4-(2-cyclopentylmethyloxy-1,1′-biphenyl-5-yl)butyrate (Intermediate 51)

The compound of the title (140 mg) was obtained by reacting with theintermediate 41 (270 mg), sodium hydride (52.0 mg, 60% abt. in oil) andcyclopentylmethyl-p-toluenesulfonate (355 mg) according to the methoddescribed in the process c-1 in example 1.

(Process a) Synthesis of4-(2-cyclopentylmethyloxy-1,1′-biphenyl-5-yl)butyric Acid (Compound 37)

The compound of the title (124 mg) was obtained by reacting with theintermediate 51 (140 mg) according to the process described in theprocess a in example 1.

Rf=0.38 (chloroform:methanol=20:1)

Example 38

4-(2-cyclohexylmethyloxy-1,1′-biphenyl-5-yl)butyric Acid (Compound 38)

(Process c-1) Synthesis of Methyl4-(2-cyclohexylmethyloxy-1,1′-biphenyl-5-yl)butyrate (Intermediate 52)

The compound of the title (336 mg) was obtained by reacting with theintermediate 41 (250 mg), bromomethyl cyclohexane (885 mg) and potassiumcarbonate anhydride (690 mg) according to the method described in theprocess c-1 in example

(Process a) Synthesis of4-(2-cyclohexylmethyloxy-1,1′-biphenyl-5-yl)butyric Acid (Compound 38)

The compound of the title (291 mg) was obtained by reacting with theintermediate 52 (336 mg) according to the process described in theprocess a in example 1.

Rf=0.38 (chloroform:methanol=20:1)

Example 39

4-[2-(4-hydroxybutyloxy)-1,1′-biphenyl-5-yl]butyric Acid (Compound 39)

(Process c-1) Synthesis of Methyl4-[2-(4-acetyloxybutyloxy)-1,1′-biphenyl-5-yl]butyrate (Intermediate 53)

The compound of the title (1.53 g) was obtained by reacting with theintermediate 41 (1.08 g), 4-bromobutyl acetate (3.90 g, Aldrich Inc.)and potassium carbonate anhydride (2.76 g) according to the methoddescribed in the process c-1 in example 1.

(Process a) Synthesis of4-[2-(4-hydroxybutyloxy)-1,1′-biphenyl-5-yl]butyric Acid (Compound 39)

The compound of the title (1.18 g) was obtained by reacting with theintermediate 53 (1.98 g) according to the process described in theprocess a in example 1.

Rf=0.50 (chloroform:methanol=10:1)

Example 40

4-[2-(3-hydroxybutyloxy)-1,1′-biphenyl-5-yl]butyric Acid (Compound 40)

(Process c-1) Synthesis of Methyl4-[2-(3-acetyloxybutyloxy)-1,1′-biphenyl-5-yl]butyrate (Intermediate 54)

The compound of the title (482 mg) was obtained by reacting with theintermediate 41 (454 mg), sodium hydride (67.2 mg, 60% abt. in oil) and3-acetyloxy-1-mesitylenesulfonyl butane [528 mg, obtained from reactionof 3-hydroxy-1-mesitylenesulfonyl butane, which was prepared from1,3-butane diol (Tokyo Chemical Ind. Co., Ltd.) and 2-mesitylenesulfonylchloride (Tokyo Chemical Ind. Co., Ltd.), with acetic anhydride inpyridine] according to the method described in the process c-1 inexample 1.

(Process a) Synthesis of4-[2-(3-hydroxybutyloxy)-1,1′-biphenyl-5-yl]butyric Acid (Compound 40)

The compound of the title (402 mg) was obtained by reacting with theintermediate 54 (480 mg) according to the process described in theprocess a in example 1.

Rf=0.49 (chloroform:methanol=10:1)

Example 41

4-[2-(2-hydroxybutyloxy)-1,1′-biphenyl-5-yl]butyric Acid (Compound 41)

(Process c-3) Synthesis of Methyl4-[2-(2-hydroxybutyloxy)-1,1′-biphenyl-5-yl]butyrate (Intermediate 55)

The compound of the title (188 mg) was obtained by reacting with theintermediate 41 (1.35 g), triethylamine (2.5 ml) and 1,2-butyleneoxide(720 mg) according to the method described in the process c-3 in example8.

(Process a) Synthesis of4-[2-(2-hydroxybutyloxy)-1,1′-biphenyl-5-yl]butyric Acid (Compound 41)

The compound of the title (180 mg) was obtained by reacting with theintermediate 55 (188 mg) according to the process described in theprocess a in example 1.

Rf=0.48 (chloroform:methanol=10:1)

Example 42

Optically Active 4-[2-(2-hydroxybutyloxy)-1,1′-biphenyl-5-yl]butyricAcid (Compound 42)

(Process p) Preparative HPLC of Optically Active Methyl4-[2-(2-hydroxybutyloxy)-1,1′-biphenyl-5-yl]butyrate (Intermediate 56)

The compound in the title (136 mg) was obtained from the intermediate 55(500 mg) according to the method described in the process p in example9.

Optical purity: 98.3%ee. Condition of preparative HPLC: CHIRALCEL OD (2cm×25 cm) column, column temp. 35° C., monitored by UV absorption at 254nm, solvent; hexane:ethanol=3.8:0.2, flow rate: 4.0 ml/min., retentiontime: 15.7 min.

(Process a) Synthesis of Optically Active4-[2-(2-hydroxybutyloxy)-1,1′-biphenyl-5-yl]butyric Acid (Compound 42)

The compound in the title (128 mg) was obtained by reacting with theintermediate

56 (136 mg) according to the process described in the process a inexample 1.

Condition for analysis: CHIRALCEL AD (0.46 cm×25 cm) column, columntemp. 35° C, monitored by UV absorption at 254 nm, solvent;hexane:ethanol trifluoroacetic acid=85:15:0.1, flow rate: 0.5 ml/min.,retention time: 16 min., optical purity: 98.3%ee.

Rf=0.48 (chloroform:methanol=10:1)

Example 43

Optically Active 4-[2-(2-hydroxybutyloxy)-1,1′-biphenyl-5-yl]butyricAcid (Compound 43)

(Process p) Preparative HPLC of Optically Active Methyl4-[2-(2-hydroxybutyloxy)-1,1′-biphenyl-5-yl]butyrate (Intermediate 57)

The compound in the title (138 mg) was obtained from the intermediate 55(500 mg) according to the method described in the process p in example9.

Optical purity: 94.2%ee. Condition of preparative HPLC: CHIRALCEL OD (2cm×25 cm) column, column temp. 35° C., monitored by UV absorption at 254nm, solvent; hexane:ethanol=3.8:0.2, flow rate: 4.0 ml/min., retentiontime: 17.9 min.

(Process a) Synthesis of Optically Active4-[2-(2-hydroxybutyloxy)-1,1′-biphenyl-5-yl]butyric Acid (Compound 43)

The compound in the title (129 mg) was obtained by reacting with theintermediate 57 (138 mg) according to the process described in theprocess a in example 1.

Condition for analysis: CHIRALCEL AD (0.46 cm×25 cm) column, columntemp. 35° C., monitored by UV absorption at 254 nm, solvent;hexane:ethanol trifluoroacetic acid=85:15:0.1, flow rate: 0.5 ml/min.,retention time: 14.6 min., optical purity: 95.8%ee.

Rf=0.48 (chloroform:methanol=10:1)

Example 44

4-(2-carboxymethyloxy-1,1′-biphenyl-5-yl)butyric Acid (Compound 44)

(Process c-1) Synthesis of Methyl4-(2-methoxycarbonymethyloxy-1,1′-biphenyl-5-yl)butyrate (Intermediate58)

The compound in the title (399 mg) was obtained by reacting theintermediate 41 (400 mg), methyl bromoacetate (1.13 g, Tokyo ChemicalInd. Co., Ltd.) and potassium carbonate anhydride (1.03 g) according tothe method described in the process c-1 in example 1.

(Process a) Synthesis of4-(2-carboxymethyloxy-1,1′-biphenyl-5-yl)butyric Acid (Compound 44)

The compound in the title (367 mg) was obtained by reacting with theintermediate 58 (399 mg) according to the process described in theprocess a in example 1.

Rf=0.4 (acetonitrile:acetic acid:water=100:2:1)

Example 45

4-[2-(2-carboxyethyloxy)-1,1′-biphenyl-5-yl]butyric Acid (Compound 45)

(Process c-4) Synthesis of Methyl4-[2-(2-cyanoethyloxy)-1,1′-biphenyl-5-yl]butyrate (Intermediate 59)

The intermediate 41 (500 mg) and copper hydroxide (10.0 mg, KantoChemical Co.) were added to acrylonitrile (4 ml, Tokyo Chemical Ind.Co., Ltd.) and refluxed. After 4 hours, triethylamine (4 drops) wasadded, and after 8 hours, toluene (5 ml) was added, then furtherrefluxed for 24 hours. The reaction mixture was cooled and acrylonitrilewas distilled off in vacuo. The residue was purified by flush columnchromatography (hexane:ethyl acetate=5:1) to obtain the compound in thetitle (206 mg).

(Process a) Synthesis of4-[2-(2-carboxyethyloxy)-1,1′-biphenyl-5-yl]butyric Acid (Compound 45)

The compound in the title (203 mg) was obtained by reacting with theintermediate 59 (206 mg) according to the process described in theprocess a in example 1.

Rf=0.21 (chromoform:methanol=10:1)

Example 46

4-[2-(3-carboxypropyloxy)-1,1′-biphenyl-5-yl]butyric Acid (Compound 46)

(Process c-1) Synthesis of Methyl4-[2-(3-ethoxycarbonylpropyloxy)-1,1′-biphenyl-5-yl]butyrate(Intermediate 60)

The compound in the title (541 mg) was obtained by reacting theintermediate 41 (400 mg), ethyl 4-bromobutylate (1.44 g, Aldrich Inc.)and potassium carbonate anhydride (1.03 g) according to the methoddescribed in the process c-1 in example 1.

(Process a) Synthesis of4-[2-(3-carboxypropyloxy)-1,1′-biphenyl-5-yl]butyric Acid (Compound 46)

The compound in the title (312 mg) was obtained by reacting with theintermediate 60 (531 mg) according to the process described in theprocess a in example 1.

Rf=0.33 (chloroform:methanol 10:1)

Example 47

4-(2-carbamoylmethyloxy-1,1′-biphenyl-5-yl)butyric Acid (Compound 47)

(Process c-1) Synthesis of Methyl4-(2-carbamoylmethyloxy-1,1′-biphenyl-5-yl)butyrate (Intermediate 61)

The compound in the title (568 mg) was obtained by reacting theintermediate 41 (540 mg), 2-bromoacetamide (1.38 g) and potassiumcarbonate anhydride (415 mg) according to the method described in theprocess c-1 in example 1.

(Process a) Synthesis of4-(2-carbamoylmethyloxy-1,1′-biphenyl-5-yl)butyric Acid (Compound 47)

The compound in the title (117 mg) was obtained by reacting theintermediate 61 (274 mg) with triethylamine (2.0 ml) in the mixture ofpurified water (4 ml) and tetrahydrofuran (10 ml) according to theprocess described in the process a in example 1. Proviso that thereaction was carried out for 10 days.

Rf=0.36 (chloroform:methanol=10:1)

Example 48

4-[2-(N,N-dimethylcarbamoylmethyloxy)-1,1′-biphenyl-5-yl]butyric acid(Compound 48)

(Process c-1) Synthesis of Methyl4-[2-(N,N-dimethylcarbamoylmethyloxy)-1,1′-biphenyl-5-yl]butyrate(Intermediate 62)

The compound in the title (455 mg) was obtained by reacting theintermediate 41 (350 mg), 2-chloro-N,N-dimethylacetamide (472 mg, Merck)and potassium carbonate anhydride (536 mg) according to the methoddescribed in the process c-1 in example 1.

(Process a) Synthesis of4-[2-(N,N-dimethylcarbamoylmethyloxy)-1,1′-biphenyl-5-yl]butyric Acid(Compound 48)

The compound in the title (366 mg) was obtained by reacting theintermediate 62 (455 mg) with triethylamine (2.0 ml) in the mixture ofpurified water (2 ml) and tetrahydrofuran (10 ml) according to theprocess described in the process a in example 1. Proviso that thereaction was carried out for 10 days. Rf 0.60 (chloroform:methanol=10:1)

Example 49

4-[2-(N,N-diethylcarbamoylmethyloxy)-1,1′-biphenyl-5-yl]butyric Acid(Compound 49)

(Process c-1) Synthesis of Methyl4-[2-(N,N-diethylcarbamoylmethyloxy)-1,1′-biphenyl-5-yl]butyrate(Intermediate 63)

The compound in the title (503 mg) was obtained by reacting theintermediate 41 (354 mg), 2-chloro-N,N-diethylacetamide (581 mg, AldrichInc.) and potassium carbonate anhydride (536 mg) according to the methoddescribed in the process c-1 in example 1.

(Process a) Synthesis of4-[2-(N,N-diethylcarbamoylmethyloxy)-1,1′-biphenyl-5-yl]butyric Acid(Compound 49)

The compound in the title (344 mg) was obtained by reacting theintermediate 63 (503 mg) with triethylamine (2.0 ml) in the mixture ofpurified water (2 ml) and tetrahydrofuran (10 ml) according to theprocess described in the process a in example 1. Proviso that thereaction was carried out for 10 days.

Rf=0.62 (chloroform:methanol=10:1)

Example 50

4-(2-butoxy-3-nitro-1,1′-biphenyl-5-yl)butyric Acid (Compound 50)

(Process n) Synthesis of Methyl4-(2-butoxy-3-nitro-1,1′-biphenyl-5-yl)butyrate (Intermediate 64)

The compound in the title (534 mg) was obtained by reacting with theintermediate 42 (652 mg) according to the process described in theprocess n in example 14.

(Process a) Synthesis of 4-(2-butoxy-3-nitro-1,1′-biphenyl-5-yl)butyricAcid (Compound 50)

The compound in the title (272 mg) was obtained by reacting with theintermediate 64 (310 mg) according to the process described in theprocess a in example 1.

Rf=0.62 (chloroform:methanol=10:1)

Example 51

4-(2-butoxy-3-formylamino-1,1′-biphenyl-5-yl)butyric Acid (Compound 51)

(Process m) Synthesis of Methyl4-(3-amino-2-butoxy-1,1′-biphenyl-5-yl)butyrate (Intermediate 65)

The compound in the title (1.45 g) was obtained by reacting with theintermediate 64 (1.59 g) according to the process described in theprocess m in example 15.

(Process 1-1) Synthesis of Methyl4-(2-butoxy-3-formylamino-1,1′-biphenyl-5-yl)butyrate (Intermediate 66)

The compound in the title (376 mg) was obtained by reacting theintermediate 65 (380 mg) and previously mixed 99% formic acid (1.0 ml)and acetic anhydride (0.32 ml) according to the process described in theprocess 1-1 in example 15.

(Process a) Synthesis of4-(2-butoxy-3-formylamino-1,1′-biphenyl-5-yl)butyric Acid (Compound 51)

The compound in the title (345 mg) was obtained by reacting with theintermediate 66 (360 mg) according to the process described in theprocess a in example 1.

Rf=0.50 (chloroform:methanol=10:1)

Example 52

4-(3-acetylamino-2-butoxy-1,1′-biphenyl-5-yl)butyric Acid (Compound 52)

(Process 1-1) Synthesis of Methyl4-(3-acetylamino-2-butoxy-1,1′-biphenyl-5-yl)butyrate (Intermediate 67)

The compound in the title (1.50 g) was obtained by reacting theintermediate 65 (1.45 g) with acetic anhydride (1.20 ml) according tothe process described in the process 1-1 in example 15.

(Process a) Synthesis of4-(3-acetylamino-2-butoxy-1,1′-biphenyl-5-yl)butyric Acid (Compound 52)

The compound in the title (1.27 g) was obtained by reacting with theintermediate 67 (1.50 g) according to the process described in theprocess a in example 1.

Rf=0.55 (chloroform:methanol=10:1)

Example 53

4-(2-butoxy-3-methylsulfonylamino-1,1′-biphenyl-5-yl)butyric Acid(Compound 53)

(Process 1-1) Synthesis of Methyl4-(2-butoxy-3-methylsulfonylamino-1,1′-biphenyl-5-yl)butyrate(Intermediate 68)

The compound in the title (420 mg) was obtained by reacting theintermediate 65 (380 mg) with methylsulfonyl chloride (0.13 ml) inpyridine (3.0 ml) according to the method described in the process 1-1in example 15. (Proviso that the reaction was performed underice-cooling for 0.5 hour and at room temperature for 1 hour).

(Process a) Synthesis of4-(2-butoxy-3-methylsulfonylamino-1,1′-biphenyl-5-yl)butyric Acid(Compound 53)

The compound in the title (370 mg) was obtained by reacting with theintermediate 68 (405 mg) according to the process described in theprocess a in example 1.

Rf=0.55 (chloroform:methanol=10:1)

Example 54

4-(2-butoxy-3-methoxy-1,1′-biphenyl-5-yl)butyric Acid (Compound 54)

(Process k) Synthesis of 2-methoxy-3-methoxybiphenyl (Intermediate 69)2-methoxymethyloxyanisole [5.23 g, prepared from 2-methoxyphenol (TokyoChemical Ind. Co., Ltd.), chloromethylmethyl ether (Tokyo Chemical Ind.Co., Ltd.) and potassium carbonate anhydride according to the methoddescribed in the process c-1 in example 1]was added to anhydrous THF (30ml) and stirred under argon atmosphere at −78° C. Hexane solution (21.4ml, Wako Pure Chem. Co.) of 1.6 molar concentration of n-butyl lithiumwas added thereto and stirred for 1 hour. The reaction mixture wasgradually changed to room temperature and stirred for 30 minutes. THFsolution of 0.5 molar concentration of zinc chloride (62.0 ml, AldrichInc.) was added thereto and stirred at room temperature for 80 minutes.Anhydrous THF solution (10 ml) of iodo benzene (6.34 g, Tokyo ChemicalInd. Co., Ltd.) and tetrakis(triphenylphosphine)palladium (0)(1.79 g)and stirred for 16 hours under light shield condition. The reactionmixture was poured into 1 N—HCl solution (100 ml) and extracted withethyl acetate (100 ml×3). The organic layer was washed with saturatedaqueous sodium bicarbonate solution and saturated aqueous sodiumchloride, dried and the solvent was distilled off in vacuo. The residuewas purified with flush column chromatography (hexane:ethylacetate=10:1) to obtain the compound in the title (5.76 g).

(Process j) Synthesis of 2-hydroxy-3-methoxybiphenyl (Intermediate 70)

The intermediate 69 (1.05 g) and 85% phosphoric acid solution (1 ml,Wako Pure Chem. Co.) were added to dioxane (10 ml) and refluxed. Thereaction mixture was cooled and water was added thereto, then extractedwith ethyl acetate. Organic layer was combined, washed with saturatedaqueous sodium chloride solution and dried. The solvent was distilledoff in vacuo. The residue was purified with flush column chromatography(hexane:ethyl acetate 9:1) to obtain the compound in the title (792 mg).

(Process c-1) Synthesis of 2-butoxy-3-methoxybiphenyl (Intermediate 71)

The compound in the title (957 mg) was obtained by reacting with theintermediate 70 (792 mg), 1-iodobutane (3.64 g) and potassium carbonateanhydride (2.73 g) according to the process described in the process c-1in example 1.

(Process f) Synthesis of Methyl4-(2-butoxy-3-methoxy-1,1′-biphenyl-5-yl)-4-oxo Butyrate (Intermediate72)

The compound in the title (516 mg) was obtained by reacting with theintermediate 71 (940 mg), aluminum chloride (978 mg) and3-carbomethoxypropionyl chloride (1.10 g) according to the processdescribed in the process f in example 28.

(Process e) Synthesis of Methyl4-(2-butoxy-3-methoxy-1,1′-biphenyl-5-yl)butyrate (Intermediate 73)

The compound in the title (303 mg) was obtained by reacting with theintermediate 72 (516 mg), conc. HCl (0.2 ml) and 10% palladium carbon(255 mg) according to the process described in the process e in example28.

(Process a) Synthesis of4-(2-butoxy-3-methoxy-1,1′-biphenyl-5-yl)butyric Acid (Compound 54)

The compound in the title (272 mg) was obtained by reacting with theintermediate 73 (303 mg) according to the process described in theprocess a in example 1.

Rf=0.52 (chloroform:methanol=10:1)

Example 55

4-(2-butoxy-1,1′-biphenyl-5-yl)butyramide (Compound 55)

(Process b-1) Synthesis of 4-(2-butoxy-1,1′-biphenyl-5-yl)butyramide(Compound 55)

The compound in the title (345 mg) was obtained by reacting with thecompound 28 (400 mg), thionyl chloride (0.39 ml) and 25% aqueous ammonia(2.0 ml) according to the process described in the process b-1 inexample 27.

Rf=0.58 (chloroform:methanol=10:1)

Example 56

4-(2-carbamoylmethyloxy-1,1′-biphenyl-5-yl)butyramide (Compound 56)

(Process b-1) Synthesis of4-(2-carbamoylmethyloxy-1,1′-biphenyl-5-yl)butyramide (Compound 56)

The compound in the title (454 mg) was obtained by reacting with thecompound 44 (630 mg), thionyl chloride (1.00 g) and 25% aqueous ammonia(20 ml) according to the process described in the process b-1in example27.

Rf=0.42 (chloroform:methanol=10:1)

Example 57

4-[2-(3-carbamoylpropyloxy)-1,1′-biphenyl-5-yl]butyramide (Compound 57)

(Process b-1) Synthesis of4-[2-(3-carbamoylpropyloxy)-1,1′-biphenyl-5-yl]butyramide (Compound 57)

The compound in the title (248 mg) was obtained by reacting with thecompound 46 (450 mg), thionyl chloride (595 mg) and 25% aqueous ammonia(10 ml) according to the process described in the process b-1 in example27.

Rf=0.37 (chloroform:methanol=10:1)

Example 58

4-[2-(4-chlorobutyloxy)-1,1′-biphenyl-5-yl]butyric Acid (Compound 58)

(Process c-1) Synthesis of Methyl4-[2-(4-chlorobutyloxy)-1,1′-biphenyl-5-yl]butyrate (Intermediate 74)

The compound in the title (302 mg) was obtained by reacting with theintermediate 41 (270 mg), 1,4-dichlorobutane (1.14 g, Tokyo ChemicalInd. Co., Ltd.) and potassium carbonate anhydride (1.00 g) according tothe process described in the process c-1 in example 1.

(Process a) Synthesis of4-[2-(4-chlorobutyloxy)-1,1′-biphenyl-5-yl]butyric Acid (Compound 58)

The compound in the title (290 mg) was obtained by reacting with theintermediate 74 (302 mg) according to the process described in theprocess a in example 1.

Rf=0.43 (chloroform:methanol=20:1)

Example 59

4-[2-(3-chlorobutyloxy)-1,1′-biphenyl-5-yl]butyric Acid (Compound 59)

(Process c-1) Synthesis of Methyl4-[2-(3-chlorobutyloxy)-1,1′-biphenyl-5-yl]butyrate (Intermediate 75)

The compound in the title (183 mg) was obtained by reacting with theintermediate 41 (270 mg), 1,3-dichlorobutane (1.12 g, Tokyo ChemicalInd. Co., Ltd.) and potassium carbonate anhydride (1.00 g) according tothe process described in the process c-1 in example 1.

(Process a) Synthesis of4-[2-(3-chlorobutyloxy)-1,1′-biphenyl-5-yl]butyric Acid (Compound 59)

The compound in the title (175 mg) was obtained by reacting with theintermediate 75 (183 mg) according to the process described in theprocess a in example 1.

Rf=0.42 (chloroform:methanol=20:1)

Example 60

4-[2-(4-bromobutyloxy)-1,1′-biphenyl-5-yl]butyric Acid (Compound 60)

(Process c-1) Synthesis of Methyl4-[2-(4-bromobutyloxy)-1,1′-biphenyl-5-yl]butyrate (Intermediate 76)

The compound in the title (325 mg) was obtained by reacting with theintermediate 41 (270 mg), 1,4-dibromobutane (648 mg, Tokyo Chemical Ind.Co., Ltd.) and anhydrous potassium carbonate (414 mg) according to theprocess described in the process c-1 in example 1.

(Process a) Synthesis of4-[2-(4-bromobutyloxy)-1,1′-biphenyl-5-yl]butyric Acid (Compound 60)

The compound in the title (292 mg) was obtained by reacting with theintermediate 76 (325 mg) according to the process described in theprocess a in example 1.

Rf=0.41 (chloroform:methanol=20:1)

Example 61

4-[2-(4,4,4-trifluorobutyloxy)-1,1′-biphenyl-5-yl]butyric Acid (Compound61)

(Process c-1) Synthesis of Methyl4-[2-(4,4,4-trifluorobutyloxy)-1,1′-biphenyl-5-yl]butyrate (Intermediate77)

The compound in the title (703 mg) was obtained by reacting with theintermediate 41 (500 mg), 1-iodo-4,4,4-trifluorobutane (2.20 g, OakwoodProducts, Inc.) and potassium carbonate anhydride (1.28 g) according tothe process described in the process c-1 in example 1.

(Process a) Synthesis of4-[2-(4,4,4-trifluorobutyloxy)-1,1′-biphenyl-5-yl]butyric Acid (Compound61)

The compound in the title (611 mg) was obtained by reacting with theintermediate 77 (690 mg) according to the process described in theprocess a in example 1.

Rf=0.40 (chloroform:methanol=20:1)

Effect of the Invention

Pharmacological action of the compound of the present invention isexplained hereinbelow.

1. Suppressive Effect on Mouse in vivo Anti-OVA-IgE Antibody Production

(1) A Method for Measurement

BALB/c mice, female, 7 weeks old, 7 mice in a group, and 9-11 mice incontrol group, were used for tests.

Suppressive effect of the compound of the present invention on IgEantibody production was evaluated according to a method described in thereference, Levin and Vaz, International Archives of Allergy and AppliedImmunology, 39: 156, 1970. Immunization was performed byintraperitoneally administering aluminium hydroxide gel (4 mg, PIERCEInc.) adsorbed with egg albumin (OVA; Sigma Inc.) 10 μg in mice. Testcompounds were suspended or dissolved in water containing 0.5%carboxymethyl cellulose, and administered orally to test animals, 100mg/kg, immediately after immunization, once a day for 5 days. Watercontaining 0.5% carboxymethyl cellulose without addition of testcompound was administered to the control group.

On day 14 after the immunization, blood was collected, and passivecutaneous anaphylaxis (PCA) reaction was performed according to themethod described in the reference, Ovary et al. International Archivesof Allergy and Applied Immunology, 48: 16, 1975, to determine theantibody production. Serum 0.1 ml, which was serially twofold dilutedwith physiological saline, was injected intracutaneously in the back ofWistar rats, male, 8 weeks old. After 24 hours, 0.5% Evans bluephysiological saline solution, which contains OVA 2 mg, 1 ml wasinjected intravenously to determine the serum boundary concentration ofpigment infiltration.

Compounds used as a control are as follows.

Control substance (1): 3-(2-methoxy-1,1′-biphenyl-5-yl)propionic acid(J. Am. Chem. Soc. 75: 2334, 1953);

Control substance (2): Methyl3-(4′-allyloxy-2-benzyloxy-1,1′-biphenyl-5-yl)propionate (Chem. Pharm.Bull. 35: 1755, 1987);

Control substance (3):[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)methyloxy-1,1′-biphenyl-5-yl]carboxylicacid (U.S. Pat. No. 5,391,817); and

Control substance (4):3-[3′-carboxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)methyloxy-1,1′-biphenyl-6-yl]propionicacid.

In addition, compounds produced by the following methods are also usedas control.

Control substance (5):N-ethyl-4-(2-butoxy-1,1′-biphenyl-5-yl)butyramide; and

Control substance (6): 4-(4-butoxy-1,1′-biphenyl-3-yl)butyric acid.Production of N-ethyl-4-(2-butoxy-1,1′-biphenyl-5-yl)butyramide [control(5)]: The compound (500 mg) was obtained by reacting with4-(2-butoxy-1,1′-biphenyl-5-yl)butyric acid (compound 28)(1.00 g),thionyl chloride (0.50 ml) and 33% ethylamine aqueous solution (TokyoChemical Ind., Ltd.) 5 ml according to the method described in theprocess b-1 in example 27.

Mass (FAB+) 340 (MH+)

Production of 4-(4-butoxy-1,1′-biphenyl-3-yl)butyric acid [control (6)]:

(Process d) Synthesis of Methyl 4-(4-hydroxy-1,1′-biphenyl-3-yl)butyrate(Intermediate 78)

The compound (310 mg) was obtained by reacting with4-(4-methoxy-1,1′-biphenyl-3-yl)butyric acid (350 mg), which wasdescribed in the reference, Fieser et al. J. Am. Chem. Soc. 58: 1783,1936, pyridine (5 ml), concentrated hydrochloric acid (5 ml), methanol(5 ml) and thionyl chloride (300 ml) according to the method describedin the process d in example 1.

Mass (FAB+) 271 (MH+)

(Process c-1) Synthesis of Methyl4-(4-butoxy-1,1′-biphenyl-3-yl)butyrate (Intermediate 79)

The compound in the title (333 mg) was obtained by reacting theintermediate 78 (300 mg), iodo butane (404 mg) and anhydrous potassiumcarbonate (277 mg) according to the method described in the process c-1in example 1.

Mass (FAB+) 327 (MH+)

(Process a) Synthesis of 4-(4-butoxy-1,1′-biphenyl-3-yl)butyric Acid[Control (6)]

The compound in the title (304 mg) was obtained by reacting with theintermediate 79 (320 mg) according to the method described in theprocess a in example 1.

Mass (FAB+) 313 (MH+)

Suppressive rate for IgE antibody production is determined by thefollowing equation.

Suppressive rate for IgE antibody production (%)$= {\left\lbrack {1 - \frac{{PCA}\quad {titer}\quad {of}\quad {test}\quad {compound}\quad {administered}\quad {group}}{{PCA}\quad {titer}\quad {of}\quad {control}\quad {group}}} \right\rbrack \times 100}$

(2) Test Results

Resuts are shown in the following table 2.

TABLE 2 Test compound Suppressive rate for IgE antibody production (%)Compound(01) 72.3 Compound(03) 50.9 Compound(04) 45.5 Compound(07) 62.0Compound(08) 58.9 Compound(12) 50.8 Compound(15) 64.2 Compound(22) 48.1Compound(25) 45.5 Compound(28) 44.5 Compound(29) 55.7 Compound(31) 49.8Compound(44) 71.5 Compound(45) 57.0 Compound(46) 64.6 Compound(47) 65.7Compound(52) 64.2 Compound(55) 55.7 Control(1) −14.4 Control(2) −11.6Control(3) −2.8 Control(4) −8.4 Control(5) −2.5 Control(6) 7.3

As shown in table 2, the compounds of the present invention in oraladministration have significant suppressive action for IgE production inBALB/c mice, which was sensitized by egg albumin. No suppressive actionfor IgE production was noted in the control compounds.

Consequently, novel biphenyl-5-alkanoic acid derivatives of the presentinvention are useful for IgE antibody production suppressor and drugsfor treatment and/or prevention of allergic diseases involved in IgEantibody. Namely, the compound of the present invention is useful fortreatment and prevention of bronchial asthma, allergic rhinitis, atopicdermatitis and allergic conjunctivitis.

2. Effect on Suppression of Mouse in vivo Foot-pad Reaction

(1) Method of Measurement

BALB/c mice, female, 7 weeks old, 5 mice in a group for test group and12-14 mice for control group were used for tests.

Effect of the compounds of the present invention on suppression of mousein vivo foot-pad reaction is evaluated by the following method.

Mice were immunized by administering intraperitoneally 4 mg of aluminiumhydroxide gel, which was adsorbed with OVA 5 μg. Test compounds weresuspended or dissolved in water containing 0.5% carboxymethyl cellulose,and were administered to test animals orally at 3-100 mg/kg, once a day,for 5 days, from immediately after immunization. For control groups,water containing 0.5% carboxymethyl cellulose without addition of thetest compound was administered.

After 10 days of immunization, OVA 10 μg was injected into the hindlimpads of mice to induce immediate type allergic foot-pad reaction.Control groups were divided into tow groups. The one was injected OVA toinduce allergic foot-pad reaction for positive control, and the otherwas injected physiological saline for negative control. After 30minutes, foot-pad volume of hidlimb of mice was measured by usingPlethysmometer (Unicom Co.) to determine increased rate for comparisonbefore induction of foot-pad reaction.

Suppressive rate for foot-pad reaction is obtained by the followingequation.

Suppressive rate for foot-pad reaction (%)$= {\left\lbrack {1 - \frac{C - B}{A - B}} \right\rbrack \times 100}$

wherein

A: increased rate of foot-pad reaction in positive control group,

B: increased rate of foot-pad reaction in negative control group,

C: increased rate of foot-pad reaction in test group (test compoundadministered group).

(2) Results

Test compounds (compound Nos. 04, 07, 22, 25, 28, 44, 47 and 55) showedsignificant suppressive action against immediate type allergic foot-padreaction in BALB/c mice, which were immunized by egg albumin, by oraladministration of the compound at 3-100 mg/kg, as compared with thepositive control.

Consequently, the novel biphenyl-5-alkanoic acid derivatives or saltthereof of the present invention are useful for treatment and/orprevention of immediate type allergic diseases caused by IgE antibody.

3. Effect on Cytokine Production From Antigen Sensitized Spleen Cells inMice

(1) Method of Measurement

Spleen cells of BALB/c mice, female, which were previously immunized byinjecting aluminium hydroxide gel adsorbed with OVA intraperitoneallytwice in 10 days interval, were stimulated by immobilized anti-mouseCD-3 monoclonal antibody (Famigen Inc.). Amounts of production ofinterleukin (IL)-4 and IL-5 in the culture supernatant after 48 hourswere assayed by using enzyme-linked immunosorbent assay (Endogen Inc.)The test compounds, 1-10 μg/ml, were added at the initial stage ofculture. No test compound added group was set as positive control, and agroup without stimulation of immobilized anti-mouse CD-3 monoclonalantibody was set as negative control.

Suppressive rate for cytokine (IL-4 and IL-5) production is calculatedby the following equation.

Suppressive rate for cytokine production (%)$= {\left\lbrack {1 - \frac{C - B}{A - B}} \right\rbrack \times 100}$

wherein

A: cytokine production of positive control group,

B: cytokine production of negative control group,

C: cytokine production of test group (test compound added group).

(2) Result

Test compounds (compound Nos. 01, 07, 11, 17, 18, 20, 22, 25, 27 and 28)showed suppressive action with 50% or more for IL-4 and IL-5 productionas a result of anti-mouyse CD-3 antibody stimulation in OVA sensitizedmouse spleen cells.

Human B cells differentiate to IgE producing cells in the presence ofIL-4 (Romagnani, S. Immunol. Today, 11: 316, 1990) and anti-IL-4antibody inhibits IgE production (Finkelman et al. Ann. Rev. Immunol. 8:303, 1990). IL-4 has known to be an essential cytokine for IgEproduction. On the other hand, IL-5 is an essential cytokine fordifferentiation and activation of eosinophils (Sanderson et al. Proc.Natl. Acad. Sci. USA, 83: 437, 1986) and has an action for infiltrationof eosinophils, which have important role in allergic inflammation, toinflammatory region (Durham et al. J. Immunol., 148: 2390, 1992).

Consequently, as the results, the above shown suppressive action for IgBproduction by the test compounds of the present invention might bepossibly based on suppressive action for IL-4 production. Further, thecompound of the present invention might have possibility to showsuppressive action against allergic inflammation bated on suppressiveaction for IL-5 production.

TABLE 1 Compound MS No. 1H-NMR(CDCl3): δ(ppm), J(Hz) m/z Inter. 2.63(2H,t, J=7.4), 2.92(2H, t, 256 1 J=7.4), 3.67(3H, s), 5.14(1H, (M+) J=1.7),6.90(1H, d, J=7.7), 7.07-7.11(2H, m), 7.34-7.52 (5H, m). Inter. 0.90(3H,t, J=7.4), 1.33-1.46 312 2 (2H, m), 1.63-1.73(2H, m), 2.64 (M+) (2H, t,J=7.4), 2.94(2H, t, J=7.4), 3.67(3H, s), 3.93(2H, t, J=6.3), 6.89(1H, d,J=8.2), 7.11 (1H, dd, J=8.2, 2.2), 7.16(1H, d, J=2.2), 7.27-7.42(3H, m),7.51-7.55(2H, m). 01 0.90(3H, t, J=7.4), 1.33-1.47 298 (2H, m),1.63-1.73(2H, m), 2.68 (M+) (2H, t, J=7.4), 2.94(2H, t, J=7.4), 3.93(2H,t, J=6.3), 6.89 (1H, d, J=8.5), 7.12(1H, dd, J=8.5, 2.4), 7.17(1H, d,J=2.4), 7.26-7.42(3H, m), 7.50-7.55(2H, m). Inter. 0.92(6H, d, J=6.9),1.94-2.05 312 3 (1H, m), 2.63(2H, t, J=7.4), 2.94 (M+) (2H, t, J=7.4),3.67(3H, s), 3.69(2H, d, J=6.3), 6.88(1H, d, J=8.5), 7.11(1H, dd, J=8.5,2.4), 7.16(1H, d, J=2.4), 7.27- 7.42(3H, m), 7.51-7.55(2H, m). 02(DMSO-d6): 0.89(6H, d, J=6.9), 298 1.83-1.98(1H, m), 2.53(2H, t, (M+)J=7.4), 2.80(2H, t, J=7.4), 3.71 (2H, d, J=6.3), 6.96-6.99(1H, m),7.13-7.18(2H, m) 7.27- 7.42(3H, m), 7.47-7.52(2H, m), 12.09(1H, br).Inter. 0.87(3H, t, J=7.1), 1.23-1.42 326 4 (4H, m), 1.64-1.75(2H, m),2.63 (M+) (2H, t, J=7.4), 2.93(2H, t, J= 7.4), 3.67(3H, s), 3.92(2H, t,J=6.6), 6.89(1H, d, J=8.5), 7.11 (1H, dd, J=8.5, 2.4), 7.16(1H, d,J=2.4), 7.27-7.42(3H, m), 7.51-7.55(2H, m). 03 0.88(3H, t, J=7.1),1.23-1.42 312 (4H, m), 1.65-1.75(2H, m), 2.69 (M+) 9(2H, t, J=7.7),2.94(2H, t, J=7.7), 3.92(2H, t, J=6.6), 6.90 (1H, d, J=8.5), 7.12(1H,dd, J=8.5, 2.4), 7.17(1H, d, J=2.4), 7.27-7.42(3H, m), 7.50-7.55(2H, m).Inter. 1.49-1.82(8H, m), 2.63(2H, t, 324 5 J=7.4), 2.93(2H, t, J=7.4),3.67 (M+) (3H, s), 4.67-4.72(1H, m), 6.89 (1H, d, J=8.2), 7.10(1H, dd,J=8.2, 2.2), 7.16(1H, d, J=2.2), 7.25-7.40(3H, m), 7.49-7.53 (2H, m). 041.52-1.80(8H, m), 2.69(2H, t, 310 J=7.4), 2.94(2H, t, J=7.4), 4.67- (M+)4.73(1H, m), 6.90(1H, d J=8.2), 7.11(1H, dd, J=8.2, 2.2), 7.17(1H, d,J=2.2), 7.28-7.40 (3H, m), 7.50-7.53(2H, m). Inter. 1.20-1.53(6H, m),1.58-1.70(2H, 338 6 m), 1.78-1.88(2H, m), 2.63 (M+) (2H, t, J=7.4),2.93(2H, t, J=7.4), 3.68(3H, s), 4.09-4.18(1H, m), 6.91(1H, d, J=8.5),7.09 (1H, dd, J=8.5, 2.5), 7.16(1H, d, J=2.5), 7.26-7.41(3H, m), 7.52-7.56(2H, m). 05 1.20-1.54(6H, m), 1.58-1.70(2H, 324 m), 1.78-1.88(2H,m), 2.69 (M+) (2H, t, J=7.4), 2.94(2H, t, J=7.4), 4.10-4.18(1H, m),6.91(1H, d, J=8.5), 7.10(1H, dd, J=8.5, 2.5), 7.17(1H, d, J=2.5), 7.25-7.41(3H, m), 7.52-7.56(2H, m). Inter. 1.19-1.33(2H, m), 1.49-1.60(4H,338 7 m), 1.69-1.79(2H, m), 2.22- (M+) 2.32(1H, m), 2.64(2H, t, J=7.7),2.93(2H, t, J=7.7), 3.67(3H, s), 3.81(2H, d, J=6.8), 6.89 (1H, d,J=8.5), 7.11(1H, dd, J=8.5, 2.5), 7.17(1H, d, J=2.5), 7.27-7.41(3H, m),7.52-7.56(2H, m). 06 1.18-1.34(2H, m), 1.48-1.58(4H, 324 m),1.68-1.80(2H, m), 2.22- (M+) 2.32(1H, m), 2.68(2H, t, J=7.4), 2.95(2H,t, J=7.4), 3.80(2H, d, J=6.8), 6.89(1H, d, J=8.2), 7.12(1H, dd, J=8.2,2.2), 7.18 (1H, d, J=2.2), 7.25-7.41(3H, m), 7.53-7.56(2H, m). Inter.0.90-1.30(5H, m), 1.60-1.81(6H, 352 8 m), 2.63(2H, t, J=7.4), 2.93(2H,t, (M+) J=7.4), 3.67(3H, s), 3.72 (2H, d, J=6.0), 6.88(1H, d, J=8.2),7.11(1H, dd, J=8.2, 2.2), 7.16(1H, d, J=2.2), 7.27-7.42 (3H, m),7.50-7.55(2H, m). 07 (DMSO-d6): 0.90-1.26(5H, m), 338 1.55-1.75(6H, m),2.53(2H, t, (M+) J=7.4), 2.80(2H, t, J=.74), 3.74 (2H, d, J=5.8),6.95-7.00(1H, m), 7.12-7.17(2H, m), 7.27-7.42 (3H, m), 7.46-7.51(2H, m).Inter. 0.95(3H, t, J=7.4), 1.45-1.58 328 9 (2H, m), 2.06(1H, d, J=3.6),2.64 (M+) (2H, t, J=7.4), 2.94(2H, t, J=7.4), 3.68(3H, s), 3.72-3.83(2H, m), 3.94-4.02(1H, m), 6.91 (1H, d, J=8.0), 7.12-7.17(2H, m),7.29-7.44(3H, m), 7.46-7.51 (2H, m). 08 (DMSO-d6): 0.85(3H, t, J=7.4),314 1.26-1.58(2H, m), 2.53(2H, t, (M+) J=7.4), 2.81(2H, t, J=7.4), 3.56-3.67(1H, m), 3.77-3.90(2H, m), 4.69(1H, d, J=5.2), 6.98- 7.02(1H, m),7.13-7.17(2H, m), 7.27-7.41(3H, m), 7.51-7.56 (2H, m), 12.09(1H, s).Inter. 0.95(3H, t, J=7.4), 1.45-1.58 328 10 (2H, m), 2.06(1H, d, J=3.6),2.64 (M+) (2H, t, J=7.4), 2.94(2H, t, J=7.4), 3.68(3H, s), 3.72-3.83(2H, m), 3.94-4.02(1H, m), 6.91 (1H, d, J=8.0), 7.12-7.17(2H, m),7.29-7.44(3H, m), 7.46-7.51 (2H, m). 09 (DMSO-d6): 0.85(3H, t, J=7.4),314 1.26-1.58(2H, m), 2.53(2H, t, (M+) J=7.4), 2.81(2H, t, J=7.4), 3.56-3.67(1H, m), 3.77-3.90(2H, m), 4.69(1H, d, J=5.2), 6.98- 7.02(1H, m),7.13-7.17(2H, m), 7.27-7.41(3H, m), 7.51-7.56 (2H, m), 12.09(1H, s).Inter. 0.95(3H, t, J=7.4), 1.45-1.58 328 11 (2H, m), 2.06(1H, d, J=3.6),2.64 (M+) (2H, t, J=7.4), 2.94(2H, t, J=7.4), 3.68(3H, s), 3.72-3.83(2H, m), 3.94-4.02(1H, m), 6.91 (1H, d, J=8.0), 7.12-7.17(2H, m),7.29-7.44(3H, m), 7.46-7.51 (2H, m). 10 (DMSO-d6): 0.85(3H, t, J=7.4)314 1.26-1.58(2H, m), 2.53(2H, t, (M+) J=7.4), 2.81(2H, t, J=7.4), 3.56-3.67(1H, m), 3.77-3.90(2H, m), 4.69(1H, d, J=5.2), 6.98- 7.02(1H, m),7.13-7.17(2H, m), 7.27-7.41(3H, m), 7.51-7.56 (2H, m), 12.09(1H, s).Inter. 1.01(3H, t, J=7.4), 2.60(2H, q, 326 12 J=7.4), 2.64(2H, t,J=7.4), 2.95 (M+) (2H, t, J=7.4), 3.68(3H, s) 4.47(2H, s), 6.76(1H, d,J=8.2), 7.12(1H, dd, J=8.2, 2.2), 7.19 (1H, d, J=2.2), 7.31-7.45(3H, m),7.52-7.56(2H, m). 11 1.01(3H, t, J=7.4), 2.60(2H, q, 314 J=7.4),2.69(2H, t, J=7.4),2.95 (M+) (2H, t, J=7.4), 4.47(2H, s) 6.76(1H, d,J=8.2), 7.14(1H, dd, J=8.2, 2.2), 7.20(1H, d, J=2.2), 7.32-7.45(3H, m),7.52-7.56(2H, m). Inter. 1.27(3H, t, J=7.1), 2.63(2H, t, 342 13 J=7.4),2.94(2H, t, J=7.4), 3.67 (M+) (3H, s), 4.23(2H, q, J=7.1), 4.56(2H, s),6.80(1H, d, J=8.5), 7.10(1H, dd, J=8.6, 2.4), 7.19 (1H, d, J=2.4),7.29-7.44(3H, m), 7.57-7.62(2H, m). 12 (DMSO-d6): 2.54(2H, t, J=7.4),300 2.80(2H, t, J=7.4), 4.66(2H, (M+) s), 6.88(1H, d, J=8.2), 7.12-7.18(2H, m), 7.27-7.43(3H, m), 7.53-7.58(2H, m). Inter. 2.65(2H, t, J=7.7),2.96(2H, t, 314 14 J=7.7), 3.68(3H, s), 4.45(2H, (MH+) s), 5.47(1H, br),6.25(1H, br), 6.86(1H, d, J=8.2), 7.16-7.19 (2H, m), 7.33-7.50(3H, m).13 (DMSO-d6): 2.63(2H, t, J=7.7) 300 2.81(2H, t, J=7.7), 4.40(2H, (MH+)s), 6.90(1H, d, J=9.3), 7.10(2H, br), 7.15-7.18(2H, m) 7.30- 7.44(3H,m), 7.56-7.59(2H, m). Inter. 0.75(3H, t, J=7.4), 1.13-1.28 358 15 (2H,m), 1.39-1.48(2H, m), 2.68 (MH+) (2H, t, J=7.4), 3.00(2H, t, J=7.4),3.57(2H, t, J=6.3), 3.69 (3H, s), 7.33-7.47(4H, m), 7.50- 7.56(3H, m).14 0.75(3H, t, J=7.4), 1.13-1.26 344 (2H, m), 1.39-1.49(2H, m), 2.74(MH+) (2H, t, J=7.4), 3.01(2H, t, J=7.4), 3.57(2H, t, J=6.3), 7.36-7.47(4H, m), 7.50-7.57(3H, m). Inter. 0.78(3H, t, J=7.4), 1.19-1.32 32716 (2H, m), 1.42-1.52(2H, m), 1.58 (M+) (1H, br), 2.62(2H, t, J=7.4),2.86(2H, t, J=7.4), 3.42(2H, t, J=6.3),3.68(3H, s), 3.92(1H, br),6.55(1H, d, J=2.2), 6.59 (1H, d, J=2.2), 7.27-7.42(3H, m), 7.53-7.57(2H,m). Inter. 0.82(3H, t, J=7.4), 1.23-1.37 370 17 (2H, m), 1.43-1.52(2H,m), 2.21 (MH+) (3H, s), 2.66(2H, t, J=7.4), 2.92(2H, t, J=7.4), 3.41(2H,t, J=6.3), 3.68(3H, s), 6.89(1H, d, J=2.2), 7.30-7.44(3H, m), 7.50-7.54(2H, m), 7.94(1H, br) 8.23(1H, d, J=2.2). 15 0.82(3H, t, J=7.4),1.21-1.36 356 (2H, m), 1.42-1.52(2H, m), 2.21 (MH+) (3H, s), 2.70(2H, t,J=7.4), 2.96 (2H, t, J=7.4), 3.41(2H, t, J=6.3), 6.91(1H, d, J=2.2),7.30- 7.44(3H, m), 7.50-7.54(2H, m), 7.98(1H, br), 8.23(1H, d, J=2.2).Inter. 0.79(3H, t, J=7.4), 1.17-1.30 405 18 (2H, m), 1.42-1.52(2H, m),2.65 (M+) (2H, t, J=7.4) 2.95(2H, t, J=7.4), 3.09(3H, s), 3.40(2H, t,J=6.6), 3.69(3H, s), 6.92(1H, d, J=2.2), 7.04(1H, br), 7.32- 7.46(4H,m), 7.49-7.4(2H, m). 16 0.78(3H, t, J=7.4), 1.16-1.30 391 (2H, m),1.42-1.52(2H, m), 2.70 (M+) (2H, t, J=7.7), 2.96(2H, t, J=7.7), 3.08(3H,s), 3.41(2H, t, J=6.6), 6.94(1H, d, J=2.2), 7.06 (1H, br), 7.32-7.46(4H,m), 7.50-7.54(2H, m). Inter. 0.68-0.85(2H, m), 0.98-1.22 397 19 3H, m),1.38-1.67(6H, m), 2.67 (M+) (2H, t, J=7.7), 2.99(2H, t, J=7.4), 3.36(2H,d, J=6.0), 3.69(3H, s), 7.36-7.55(7H, m). Inter. 0.77-1.20(5H, m),1.40-1.70(7H, 367 20 m), 2.62(2H, t, J=7.7), 2.85 (M+) (2H, t, J=7.4),3.21(2H, d, J=6.0), 3.68(3H, s), 3.91(1H, br), 6.55(1H, d, J=1.9),6.59(1H, d, J=1.9), 7.27-7.41(3H, m), 7.52-7.56(2H, m). Inter.0.86-1.33(5H, m), 1.40-1.75(6H, 410 21 m), 2.20(3H, s), 2.65(2H, t,(MH+) J=7.7), 2.95(2H, t, J=7.7), 3.19 (2H, d, J=5.8), 3.68(3H, s),6.89(1H, d, J=2.2), 7.31-7.43 (3H, m), 7.50-7.54(2H, m), 7.96 (1H, br),8.22(1H, d, J=2.2). 17 (DMSO-d6): 0.68-1.16(6H, m), 396 1.35-1.62(6H,m), 2.08(3H, s), (MH+) 2.53(2H, t, J=7.7), 2.80(2H, t, J=7.4), 3.17(2H,d, J=5.8), 6.96(1H, br), 7.32-7.51(5H, m), 7.64(1H, br), 9.13(1H, br).Inter. 0.77-1.31(6H, m), 1.40-1.75(6H, 445 22 m), 2.65(2H, t, J=7.4),2.95 (M+) (2H, t, J=7.4), 3.00(3H, s), 3.19 (2H, d, J=6.0), 3.69(3H, s),6.93(1H, d, J=2.2), 7.01(1H, br), 7.31-7.53(6H, m). 18 0.75-1.30(5H, m),1.40-1.72(6H, 432 m), 2.70(2H, t, J=7.7), 2.96 (MH+) (2H, t, J=7.4),3.08(3H, s), 3.19 (2H, d, J=5.8), 6.93(1H, d, J=1.9), 7.03(1H, br),7.32-7.53 (6H, m). Inter 0.77-1.26(5H, m), 1.40-1.72(6H, 468 23 m),2.24(3H, s), 2.66(2H, t, (MH+) J=7.4), 2.96(2H, t, J=7.4), 3.20 (2H, d,J=6.0), 3.68(3H, s), 4.73(2H, s), 6.94(1H, d, J=2.2), 7.32-7.44(3H, m),7.49-7.54 (2H, m), 8.26(1H, d, J=2.2), 8.65(1H, br). 19 (DMSO-d6):0.75-1.21(5H, m), 412 1.40-1.66(6H, m), 2.54(2H, t, (MH+) J=7.7),2.82(2H, t, J=7.4), 3.17 (2H, d, J=5.8), 4.01(2H, s), 6.94(1H, d,J=2.2), 7.35-7.54 (5H, m), 8.21(1H, d, J=1.9), 9.34 (1H, s). Inter.0.77-1.24(5H, m), 1.36-1.72(6H, 439 24 m), 2.65(2H, t, J=7.7), 2.93(MH+) (2H, t, J=7.4), 3.06(6H, s), 3.19 (2H, d, J=6.3), 3.67(3H, s),6.79(1H, d, J=2.5), 7.29(1H, br), 7.31-7.43(3H, m), 7.49-7.53 (2H, m),8.08(1H, d, J=2.2). 20 0.77-1.24(5H, m), 1.36-1.70(6H, 425 m), 2.70(2H,t, J=7.7), 2.94 (MH+) (2H, t, J=7.4), 3.07(6H, s), 3.19 (2H, d, J=6.0),6.81(1H, d, J=2.2), 7.29(1H, br), 7.31-7.43 (3H, m), 7.49-7.53(2H, m),8.06 (1H, d, J=2.2). Inter. 0.79-1.27(5H, m), 1.44-1.72(6H, 474 25 m),2.64(2H, t, J=7.4), 2.92 (M+) (6H, s), 2.94(2H, t, J=7.4), 3.20 (2H, d,J=5.8), 3.69(3H, s), 6.87(1H, d, J=2.2), 6.98(1H, br), 7.28(1H, d,J=2.2), 7.32- 7.44(3H, m), 7.48-7.54(2H, m). 21 0.79-1.28(1H, m),1.42-1.72(6H, 461 m), 2.69(2H, t, J=7.4), 2.91 (MH+) (6H, s), 2.94(2H,t, J=7.4), 3.21 (2H, d, J=6.0), 6.88(1H, d, J=2.2), 6.99(1H, br),7.30(1H, d, J=2.2), 7.32-7.44(3H, m), 7.48-7.53(2H, m). Inter.0.78-1.28(5H, m), 1.40-1.72(6H, 411 26 m), 2.65(2H, t, J=7.7), 2.94(MH+) 4(2H, t, J=7.7), 3.20(2H, d, J= 6.0), 3.68(3H, s), 4.75(2H, br),6.86(1H, d, J=2.2), 7.05(1H, br), 7.30-7.43(3H, m), 7.48- 7.53(2H, m),7.80(1H, d, J=2.2). 22 (DMSO-d6): 0.50-0.70(2H, m), 397 0.90-1.18(3H,m), 1.42-1.65 (MH+) (6H, m), 2.51(2H, t, J=7.7), 2.77 (2H, t, J=7.7),3.12(2H, d, J= 6.3), 6.28(2H, br), 6.74(1H, d, J=2.2), 7.30-7.50(6H, m),7.78 (1H, br), 7.92(1H, d, J=2.2). Inter. 1.06-1.38(5H, m), 1.69-1.97375 27 (6H, m), 3.88-3.90(5H, m), 7.39 (MH+) (1H, d, J=1.6), 7.85(1H, d,J=1.6), 9.82(1H, s). Inter. 0.71-0.90(2H, m), 1.02-1.20(3H, 325 28 m),1.43-1.65(6H, m), 3.58 (MH+) (2H, d, J=6.0), 3.96(3H, s), 7.34- 7.55(7H,m), 9.93(1H, s). Inter. 0.68-0.86(2H, m), 1.02-1.20(3H, 394 29 m),1.34(3H, t, J=7.1), 1.43- (M+) 1.64(6H, m), 3.49(2H, d, J=6.3), 3.92(3H,s), 4.26(2H, q, J= 7.1), 6.38(1H, d, J=15.9), 7.06 (1H, d, J=1.9),7.13(1H, d, J= 1.9), 7.30-7.43(3H, m), 7.49- 7.53(2H, m), 7.66(1H, d,J=15.9). Inter. 0.68-0.80(2H, m), 1.02-1.18(3H, 396 30 m), 1.24(3H, t,J=7.1), 1.44- (M+) 1.63(6H, m), 2.64(2H, t, J=7.4), 2.94(2H, t, J=7.4),3.41(2H, d, J=6.3), 3.87(3H, s), 4.14 (2H, q, J=7.1), 6.74-6.78(2H, m),7.26-7.41(3H, m), 7.49-7.53 (2H, m). 23 0.68-0.80(2H, m), 1.02-1.17(3H,368 m), 1.42-1.63(6H, m), 2.71 (M+) (2H, t, J=7.4), 2.96(2H, t, J=7.4),3.41(2H, d, J=6.3), 3.87(3H, s), 6.75-6.79(2H, m), 7.28- 7.41(3H, m),7.49-7.53(2H, m). Inter. 0.80-0.94(2H, m), 1.02-1.26 368 31 (3H, m)1.43-1.70(6H, m), 2.64 (M+) (2H, t, J=7.4), 2.91(2H, t, J=7.4), 3.23(2H,d, J=6.0), 3.68(3H, s), 5.85(1H, s), 6.70(1H, d, J=2.2), 6.80(1H, d,J=2.2), 7.31- 7.43(3H, m), 7.52-7.56(2H, m). 24 0.80-0.94(2H, m),1.02-1.28(3H, 354 m), 1.47-1.70(6H, m), 2.68 (M+) (2H, t, J=7.4),2.91(2H, t, J=7.4), 3.24(2H, d, J=6.0), 6.71(1H, d, J=2.2), 6.81(1H, d,J=2.2), 7.31-7.43(3H, m), 7.52-7.56 (2H, m). Inter. 1.06-1.40(5H, m),1.70-1.94(6H, 296 32 m), 3.90(2H, d, J=6.0), 6.97 (M+) (1H, d, J=8.5),7.79(1H, dd, J= 8.5, 2.2), 8.07(1H, d, J=2.2), 9.83(1H, s). Inter.0.90-1.31(5H, m), 1.59-1.83(6H, 400 33 m), 3.86(2H, d, J=6.0), 3.71 (M+)(2H, d, J=6.0), 5.12(2H, s), 7.00- 7.06(3H, m), 7.26-7.51(7H, m),7.79-7.84(2H, m), 9.91(1H, s). Inter. 0.95-1.32(5H, m), 1.60-1.82 456 34(6H, m), 3.78-3.80(5H, m), 5.11 (M+) (2H, s), 6.33(1H, d, J=15.9), 6.92(1H, d, J=8.5), 7.00-7.05(2H, m), 7.18-7.50(9H, m), 7.68 (1H, d,J=15.9). Inter. 0.90-1.34(5H, m), 1.54-1.83 368 35 (6H, m), 2.63(2H, t,J=7.4), 2.92 (M+) (2H, t, J=7.4), 3.68(3H, s), 3.71 (2H, d, J=6.0),4.89(1H, br), 6.84-6.90(3H, m), 7.06-7.15 (2H, m), 7.41-7.46(2H, m). 250.86-1.30(5H, m), 1.56-1.80(6H, 354 m), 2.68 (2H, t, J=7.4), 2.93 (M+)(2H, t, J=7.4), 3.71(2H, d, J= 6.0), 6.83-6.89(3H, m), 7.07- 7.14(2H,m), 7.39-7.46(2H, m). Inter. 0.96-1.32(5H, m), 1.65-1.83(6H, 324 36 m),3.85-3.87(5H, m), 6.94- (M+) 6.98(2H, m), 7.04(1H, d, J=8.5),7.47-7.51(2H, m), 7.79-7.84 (2H, m), 9.92(1H, s). Inter. 0.95-1.30(5H,m), 1.65-1.81(6H, 380 37 m), 3.79-3.86(8H, m), 6.34 (M+) (1H, d,J=15.9), 6.92-6.97(3H, m), 7.41-7.51(4H, m), 7.68(1H, d, J=15.9). Inter.0.92-1.30(5H, m), 1.60-1.80(6H, 382 38 m), 2.63(2H, t, J=7.4), 2.92 (M+)(2H, t, J=7.4), 3.67(3H, s), 3.72 (2H, d, J=6.0), 3.85(3H, s), 6.86(1H,d, J=8.2), 6.90-6.96 (2H, m), 7.08(1H, dd, J=8.2, 2.2), 7.14(1H, d,J=2.2), 7.45- 7.50(2H, m). 26 0.92-1.30(5H, m), 1.60-1.80(6H, 368 m),2.68(2H, t, J=7.4), 2.93 (M+) (2H, t, J=7.4), 3.72(2H, d, J= 6.0),3.85(3H, s), 6.87(1H, d, J=8.2), 6.90-6.96(2H, m), 7.09 (1H, dd, J=8.2,2.2), 7.15(1H, d, J=2.2), 7.45-7.50(2H, m). 27 0.90-1.32(5H, m),1.57-1.80(6H, 338 m), 2.53(2H, t, J=7.4), 2.96 (MH+) (2H, t, J=7.4),3.72(2H, d, J= 5.8), 6.88(1H, d, J=8.2), 7.13 (1H, dd, J=8.2, 2.2),7.17(1H, d, J=2.2), 7.25-7.42(3H, m), 7.50- 7.55(2H, m). Inter. 2.76(2H,t, J=6.6), 3.60(2H, t, 298 39 J=6.6), 3.70(3H, s), 3.88(3H, (M+) s),7.02(1H, d, J=8.5), 7.33- 7.45(3H, m), 7.50-7.53(2H, m), 7.97(1H, d,J=2.2), 8.00(1H, dd, J=8.5, 2.2). Inter. 1.92-2.02(2H, m), 2.39(2H, t,284 40 J=7.4), 2.66(2H, t, J=7.4), 3.79 (M+) (3H, s), 5.10(1H, s),6.89-6.92 (1H, m), 7.11-7.14(2H, m) 7.29-7.43(3H, m), 7.51-7.54 (2H, m).Inter. 1.90-2.00(2H, m), 2.35(2H, t, 270 41 J=7.4), 2.62(2H, t, J=7.4),3.66 (M+) (3H, s), 5.10(1H, s), 6.91(1H, d, J=7.7), 7.05-7.09(2H, m),7.37-7.52(5H, m). Inter. 0.90(3H, t, J=7.4), 1.34-1.46 326 42 (2H, m),1.64-1.73(2H, m), 1.91- (M+) 2.01(2H, m), 2.35(2H, t, J=7.4), 2.63(2H,t, J=7.4), 3.66(3H, s), 3.93(2H, t, J=6.3), 6.89 (1H, d, J=8.2),7.09(1H, dd, J= 2.5, 8.2), 7.14(1H, d, J=2.5), 7.27-7.42(3H, m),7.52-7.56 (2H, m). 28 0.90(3H, t, J=7.4), 1.33-1.47 312 (2H, m),1.62-1.72(2H, m), 1.92- (M+) 2.02(2H, m), 2.39(2H, t, J=7.4), 2.66(2H,t, J=7.4), 3.93(2H, t, J=6.3), 6.90(1H, d, J=8.5), 7.10(1H, dd, J=2.5,8.5). 7.14 (1H, d, J=2.5), 7.30-7.41 (3H, m), 7.53-7.56(2H, m). Inter.0.93(6H, d, J=6.3), 1.91-2.04 326 43 (3H, m), 2.35(2H, t, J=7.4), 2.63(M+) (2H, t, J=7.4), 3.66(3H, s), 3.69(2H, d, J=6.3), 6.88(1H, d,J=8.2), 7.09(1H, dd, J=8.2, 2.2), 7.14(1H, d, J=2.2), 7.27- 7.41(3H, m),7.52-7.56(2H, m). 29 0.93(6H, d, J=6.3), 1.92-2.04 312 (3H, m), 2.39(2H,t, J=7.4), 2.66 (M+) (2H, t, J=7.4), 3.69(2H, d, J= 6.3), 6.88(1H, d,J=8.2), 7.09 (1H, dd, J=8.2, 2.2), 7.15(1H, d, J=2.2), 7.27-7.41(3H, m),7.53-7.56(2H, m). Inter. 0.86(3H, t, J=7.4), 1.18(3H, d, 326 44 J=6.0),1.44-1.71(2H, m), 1.91- (M+) 2.01(2H, m), 2.35(2H, t, J= 7.4), 2.63(2H,t, J=7.4), 3.66 (3H, s), 4.16-4.22(1H, m), 6.89 (1H, d, J=8.2), 7.07(1H,dd, J= 8.2, 2.2), 7.13(1H, d, J=2.2), 7.25-7.41(3H, m), 7.52-7.56 (2H,m). 30 0.86(3H, t, J=7.4), 1.17(3H, d, 311 J=6.0), 1.44-1.71(2H, m),1.91- (M—H—) 2.01(2H, m), 2.38(2H, t, J= 7.4), 2.64(2H, t, J=7.4), 4.12-4.24(1H, m), 6.89(1H, d, J=8.5), 7.07(1H, dd, J=8.5, 2.2), 7.13 (1H, d,J=2.2), 7.25-7.40 (3H, m), 7.52-7.55(2H, m). Inter. 0.88(3H, t, J=7.1),1.26-1.40 340 45 (4H, m), 1.65-1.75(2H, m), 1.91- (M+) 2.01(2H, m),2.35(2H, t, J=7.4), 2.63(2H, t, J=7.4), 3.66 (3H, s), 3.92(2H, t,J=6.6), 6.89, (1H, d, J=8.2), 7.09(1H, dd, J= 8.2, 2.2), 7.14(1H, d,J=2.2), 7.27-7.41(3H, m), 7.52-7.56 (2H, m). 31 0.88(3H, t, J=7.1),1.26-1.38 326 (4H, m), 1.65-1.75(2H, m), 1.91- (M+) 2.01(2H, m),2.39(2H, t, J=7.4), 2.65(2H, t, J=7.4), 3.92(2H, t, J=6.6), 6.89(1H, d,J=8.5), 7.09(1H, dd, J=8.5, 2.2), 7.14 (1H, d, J=2.2), 7.27-7.41 (3H,m), 7.51-7.55(2H, m). Inter. 0.85(3H, t, J=7.4), 1.17(3H, d, 340 46J=6.3), 1.25-1.69(4H, m), 1.91- (M+) 2.01(2H, m), 2.35(2H, t, J= 7.4),2.63(2H, t, J=7.4), 3.66 (3H, s), 4.19-4.30(2H, m), 6.89 (1H, d, J=8.2),7.07(1H, dd, J= 2.2, 8.2), 7.13(1H, d, J=2.2), 7.25-7.40(3H, m),7.52-7.55 (2H, m). 32 0.86(3H, t, J=7.4), 1.17(3H, d, 326 J=6.3),1.25-1.69(4H, m), 1.92- (M+) 2.02(2H, m), 2.40(2H, t, J= 7.4), 2.65(2H,t, J=7.4), 4.19- 4.30(2H, m), 6.89(1H, d, J=8.2), 7.08(1H, dd, J=2.2,8.2), 7.13 (1H, d, J=2.2), 7.26-7.40 (3H, m), 7.51-7.54(2H, m). Inter.0.84-0.93(6H, m), 1.09-1.82 340 47 (3H, m), 1.91-2.01(2H, m), 2.35 (M+)(2H, t, J=7.4), 2.63(2H, t, J=7.4), 3.66(3H, s), 3.70-3.79(2H, m),6.88(1H, d, J=8.2), 7.09 (1H, dd, J=8.2, 2.2), 7.14(1H, d, J=2.2),7.25-7.41(3H, m), 7.51-7.55(3H, m). 33 0.84-0.93(6H, m), 1.11-1.82 326(3H, m), 1.91-2.01(2H, m), 2.36 (M+) (2H, t, J=7.4), 2.64(2H, t, J=7.4),3.66-3.81(2H, m), 6.88(1H, d, J=8.2), 7.08(1H, dd, J=8.2, 2.2), 7.14(1H,d, J=2.2), 7.26- 7.40(3H, m), 7.51-7.55(3H, m). Inter. 0.87(6H, d,J=6.6), 1.58(2H, q, 340 48 J=7.4), 1.65-1.79(1H, m), (M+) 1.91-2.01(2H,m), 2.35(2H, t, J= 7.4), 2.63(2H, t, J=7.4), 3.66 (3H, s), 3.95(2H, t,J=6.6), 6.90 90(1H, d, J=8.2), 7.09(1H, dd, J=2.2, 8.2), 7.14(1H, d,J=2.2), 7.27-7.41(3H, m), 7.51-7.55 (2H, m). 34 0.87(6H, d, J=6.6),1.59(2H, q, 326 J=6.6), 1.65-1.78(1H, m), 1.92- (M+) 2.02(2H, m), 2.39(2H, t, J= 7.4), 2.65(2H, t, J=7.4), 3.95 (2H, t, J=6.6), 6.90(1H, d,J=8.2), 7.09(1H, dd, J=2.2, 8.2), 7.14(1H, d, J=2.2), 7.27-7.41 (3H, m),7.51-7.65(2H, m). Inter. 1.48-1.84(8H, m), 1.91-2.01(2H, 338 49 m),2.35(2H, t, J=7.4), 2.63 (M+) (2H, t, J=7.4), 3.66(3H, s), 4.67-4.72(1H, m), 6.89(1H,d, J= 8.2), 7.07(1H, dd, J=8.2, 2.2), 7.13(1H, d,J=2.2), 7.25-7.40 (3H, m), 7.60-7.54(2H, m). 35 1.48-1.84(8H, m),1.92-2.02(2H, 324 m), 2.39(2H, t, J=7.4), 2.65 (M+) (2H, t, J=7.4),4.67-4.72(1H, m), 6.89(1H, d, J=8.2), 7.08(1H, dd, J=8.2, 2.2), 7.14(1H,d, J=2.2), 7.27-7.40(3H, m),7.50- 7.54(2H, m). Inter. 1.20-1.88(10H, m),1.90-2.01 352 50 (2H, m), 2.34(2H, t, J=7.4), 2.62 (M+) (2H, t, J=7.4),3.65(3H, s), 4.08-4.16(1H, m), 6.90(1H, d, J=8.5), 7.06(1H, dd, J=8.5,2.2), 7.14(1H, d, J=2.2), 7.25-7.40 (3H, m), 7.50-7.57(2H, m). 361.20-1.86(10H, m), 1.90-2.02 338 (2H, m), 2.39(2H, t, J=7.4), 2.65 (M+)(2H, t, J=7.4), 4.08-4.16(1H, m), 6.91(1H, d, J=8.5), 7.07 (1H, dd,J=8.5, 2.2), 7.14(1H, d, J=2.2), 7.25-7.41(3H, m), 7.54-7.57(2H, m).Inter. 1.21-1.34(2H, m), 1.48-1.60 352 51 (4H, m), 1.69-1.79(2H, m),1.91- (M+) 2.01(2H, m), 2.22-2.32(1H, m), 2.35(2H, t, J=7.4), 2.63(2H,t, J=7.4), 3.66(3H, s), 3.81 (2H, d, J=6.6), 6.89(1H, d, J = 8.2),7.09(1H, dd, J=8.2, 2.2), 7.14(1H, d, J=2.2), 7.27-7.41 (3H, m),7.53-7.57(2H, m). 37 1.23-1.33(2H, m), 1.49-1.60 338 (4H, m),1.69-1.79(2H, m), 1.91- (M+) 2.01(2H, m), 2.22-2.32(1H, m), 2.39(2H, t,J=7.4), 2.65(2H, t, J=7.4), 3.80(2H, d, J=6.6), 6.88(1H, d, J=8.2),7.09(1H, dd, J=8.2, 2.2), 7.14(1H, d, J= 2.2), 7.26-7.41(3H, m), 7.52-7.56(2H, m). Inter. 0.93-1.28(5H, m), 1.64-1.77 366 52 (6H, m),1.90-2.00(2H, m), 2.35 (M+) (2H, t, J=7.4), 2.63(2H, t, J=7.4), 3.66(3H,s), 3.72(2H, d, J= 6.0), 6.88(1H, d, J=8.2), 7.09 (1H, dd, J=8.2, 2.2),7.14(1H, d, J=2.2), 7.26-7.42(3H, m), 7.52-7.56(2H, m). 38 0.96-1.26(5H,m), 1.68-1.77 352 (6H, m), 1.92-2.02(2H, m), 2.39 (M+) (2H, t, J=7.4),2.66(2H, t, J=7.4), 3.72(2H, d, J=6.0), 6.88 (1H, d, J=8.2), 7.09(1H,dd, J= 8.2, 2.2), 7.14(1H, d, J=2.2), 7.28-7.41(3H, m), 7.53-7.55 (2H,m). Inter. 1.66-1.81(4H, m), 0.86(3H, t, 384 53 J=7.4), 1.91-2.01(2H,m), 2.03 (M+) 3(3H, s), 2.35(2H, t, J=7.4), 2.64 (2H, t, J=7.4),3.66(3H, s), 3.95(2H, t, J=5.8), 4.03(2H, t, J=6.3), 6.89(1H, d, J=8.2),7.09(1H, dd, J=8.2, 2.2), 7.14 (1H, d, J=2.2), 7.26-7.41(3H, m),7.51-7.54(2H, m). 39 1.58-1.67(2H, m), 1.74-1.83 328 2H, m),1.91-2.01(2H, m), 2.39 (M+) (2H, t, J=7.4), 2.66(2H, t, J=7.4), 3.58(2H,t, J=6.3), 3.97 (2H, t, J=6.3), 6.90(1H, d, J=8.2), 7.10(1H, dd, J=8.2,2.2), 7.14(1H, d, J=2.2), 7.26-7.42 (3H, m), 7.50-7.53(2H, m). Inter.1.20(3H, d, J=6.3), 1.90-2.00 384 54 (7H, m), 2.35(2H, t, J=7.4), 2.63(M+) (2H, t, J=7.4), 3.66(3H, s), 3.96(2H, t, J=6.3), 4.98-5.09 (1H, m),6.88(1H, d, J=8.2), 7.09(1H, dd, J=8.2, 2.2), 7.14 (1H, d, J=2.2),7.28-7.53(5H, m). 40 1.15(3H, d, J=6.3), 1.83(2H, q, 328 J=6.3),1.91-2.01(2H, m), 2.39 (M+) (2H, t, J=7.4), 2.66(2H, t, J= 7.4),3.84-3.97(1H, m), 3.99- 4.17(2H, m), 6.92(1H, d, J=8.2), 7.10-7.13(2H,m), 7.28-7.50 (5H, m). Inter. 0.94(3H, t, J=7.4), 1.44-1.54 342 55 (1H,m), 1.91-2.01(2H, m), 2.13 (M+) (1H, br), 2.34(2H, t, J=7.4), 2.63(2H,t, J=7.4), 3.65(3H, s), 3.72-3.78(2H, m), 3.94-4.02 (1H, m), 6.90(1H, d,J=8.2), 7.10(1H, dd, J=8.2, 2.2), 7.14 (1H, d, J=2.2), 7.28-7.42(3H, m),7.47-7.51(2H, m). 41 0.95(3H, t, J=7.4), 1.45-1.55 328 (2H, m),1.91-2.01(2H, m), 2.09 (M+) (1H, br), 2.38(2H, t, J=7.4), 2.66(2H, t,J=7.4), 3.73-3.80 (2H, m), 3.94-4.02(1H, m), 6.91 (1H, d, J=8.2),7.11(1H, dd, J= 8.2, 2.2), 7.14(1H, d, J=2.2), 7.29-7.43(3H, m),7.48-7.51 (2H, m). Inter. 0.94(3H, t, J=7.4), 1.44-1.54 342 56 (1H, m),1.91-2.01(2H, m), 2.13 (M+) (1H, br), 2.34(2H, t, J=7.4), 2.63(2H, t,J=7.4), 3.65(3H, s), 3.72-3.78(2H, m), 3.94-4.02 (1H, m), 6.90(1H, d,J=8.2), 7.10(1H, dd, J=8.2, 2.2), 7.14 (1H, d, J=2.2), 7.28-7.42(3H, m),7.47-7.51(2H, m). 42 0.95(3H, t, J=7.4), 1.45-1.55 328 (2H, m),1.91-2.01(2H, m), 2.09 (M+) (1H, br), 2.38(2H, t, J=7.4), 2.66(2H, t,J=7.4), 3.73-3.80 (2H, m), 3.94-4.02(1H, m), 6.91 (1H, d, J=8.2),7.11(1H, dd, J= 8.2, 2.2), 7.14(1H, d, J=2.2), 7.29-7.43(3H, m),7.48-7.51 (2H, m). Inter. 0.94(3H, t, J=7.4), 1.44-1.54 342 57 (2H, m),1.91-2.01(2H, m), 2.13 (M+) (1H, br), 2.34(2H, t, J=7.4), 2.63(2H, t,J=7.4), 3.65(3H, s), 3.72-3.78(2H, m), 3.94-4.02 (1H, m), 6.90(1H, d,J=8.2), 7.10(1H, dd, J=8.2, 2.2), 7.14 (1H, d, J=2.2), 7.28-7.42(3H, m),7.47-7.51(2H, m). 43 0.95(3H, t, J=7.4), 1.45-1.55 328 (2H, m),1.91-2.01(2H, m), 2.09 (M+) (1H, br), 2.38(2H, t, J=7.4), 2.66(2H, t,J=7.4), 3.73-3.80 (2H, m), 3.94-4.02(1H, m), 6.91 (1H, d, J=8.2),7.11(1H, dd, J= 8.2, 2.2), 7.14(1H, d, J=2.2, 7.29-7.43(3H, m),7.48-7.51 (2H, m). Inter. 1.91-2.01(2H, m), 2.35(2H, t, 342 58 J=7.4),2.64(2H, t, J=7.4), 3.66 (M+) (3H, s), 3.77(3H, s), 4.57(2H, s),6.80(1H, d, J=8.2), 7.09 (1H, dd, J=8.2, 2.2), 7.16(1H, d, J=2.2),7.29-7.44(3H, m), 7.57-7.61(2H, m). 44 (CD3OD): 1.86-1.96(2H, m), 2.31314 (2H, t, J=7.4), 2.64(2H, t, J= (M+) 7.4), 4.58(2H, s), 6.89(1H, d,J=8.2), 7.10-7.14(2H, m), 7.25-7.44(3H, m), 7.54-7.58(2H, m). Inter.1.91-2.01(2H, m), 2.34(2H, t, 323 59 J=7.4), 2.62-2.69(4H, m), 3.66 (M+)(3H, s), 4.09(2H, t, J=6.6), 6.88(1H, d, J=8.2), 7.11(1H, dd, J=8.2,2.2), 7.17(1H, d, J=2.2), 7.29-7.44(3H, m), 7.52-7.56(2H, m). 45(CD3OC): 1.86-1.96(2H, m), 2.31 328 (2H, t, J=7.4), 2.61-2.67 (M+) (4H,m), 4.19(2H, t, J=6.0), 6.98- 7.01(1H, m), 7.12-7.15(2H, m),7.22-7.37(3H, m), 7.45-7.49 (2H, m) Inter. 1.24(3H, t, J=7.1), 1.91-2.06384 60 (4H, m), 2.35(2H, t, J=7.4), 2.39 (M+) (2H, t, J=7.4), 2.63(2H,t, J= 7.4), 2.66(3H, s), 3.97(2H, t, J=6.0), 4.10(2H, q, J=7.1),6.89(1H, d, J=8.2), 7.09(1H, dd, J=8.2, 2.5), 7.14(1H, d, J=2.5),7.28-7.42(3H, m), 7.49-7.53 (2H, m). 46 1.94-2.05(4H, m), 2.37(2H, t,342 J=7.4), 2.44(2H, t, J=7.4), 2.66 (M+) (2H, t, J=7.4), 3.99(2H, t, J=6.0), 6.89(1H, d, J=8.2), 7.08-7.12(2H, m), 7.28-7.41 (3H, m),7.48-7.51(2H, m). Inter. 1.91-2.02(2H, m), 2.36(2H, t, 328 61 J=7.4),2.66(2H, t, J=7.4), (M+) 3.67(3H, s), 4.45(2H, s), 6.85- 6.88(1H, m),7.13-7.17(2H, m), 7.32-7.51(5H, m). 47 (DMSO-d6): 1.66-1.76(2H, m), 3142.21(2H, t, J=7.4), 2.57(2H, t, (MH+) J=7.4), 4.40(2H, s), 6.89-6.92(1H, m), 7.10-7.15(4H, m), 7.30-7.44(3H, m), 7.56-7.59 (2H, m), 11.83,(1H, br). Inter. 1.90-2.00(2H, m), 2.35(2H, t, 356 62 J=7.4), 2.63(2H,t, J=7.4), 2.88 (MH+) (3H, s), 2.92(3H, s), 3.66(3H, s), 4.63(2H, s),6.93(1H, d, J=8.2), 7.09(1H, dd, J=8.2, 2.2), 7.14(1H, d, J=2.2), 7.26-7.42(3H, m), 7.52-7.55(2H, m). 48 1.91-2.01(2H, m), 2.38(2H, t, 342J=7.4), 2.65(2H, t, J=7.4), (MH+) 2.87(3H, s), 2.91(3H, s), 4.63(2H, s),6.93(1H, d, J=8.2), 7.10 (1H, dd, J=8.2, 2.2), 7.13(1H, d, J=2.2),7.26-7.41(3H, m), 7.50-7.54(2H, m). Inter. 0.98(3H, t, J=7.1), 1.09(3H,t, 384 63 J=7.1), 1.90-2.00(2H, m), 2.35 (MH+) (2H, t, J=7.1), 2.63(2H,t, J= 7.1), 3.21(2H, q, J=7.1), 3.35 (2H, q, J=7.1), 3.66(3H, s), 4.60(2H, s), 6.92(1H, d, J=8.2), 7.09(1H, dd, J=8.2, 2.2), 7.14 (1H, d,J=2.2), 7.27-7.41(3H, m), 7.52-7.56(2H, m). 49 0.97(3H, t, J=7.1),1.09(3H, t, 370 J=7.1), 1.91-2.01(2H, m), 2.38 (MH+) (2H, t, J=7.1),2.65(2H, t, J= 7.1), 3.21(2H, q, J=7.1), 3.35 (2H, q, J=7.1), 4.60(2H,s) 6.92(1H, d, J=8.2), 7.09(1H, dd, J=8.2, 2.2), 7.14(1H, d, J=2.2),7.26-7.41(3H, m), 7.52- 7.55(2H, m). Inter. 0.75(2H, t, J=7.4),1.14-1.28 372 64 (2H, m), 1.39-1.49(2H, m), (MH+) 1.94-2.05(2H, m),2.38(2H, t, J=7.4), 2.70(2H, t, J=7.4), 3.57 (2H, t, J=6.3), 3.68(3H,s), 7.34- 7.47(4H, m), 7.50-7.56(3H, m). 50 0.75(3H, t, J=7.4),1.13-1.26 358 (2H, m), 1.39-1.49(2H, m), 1.95- (MH+) 2.05(2H, m),2.43(2H, t, J=7.4), 2.73(2H, t, J=7.4), 3.57 (2H, t, J=6.3),7.35-7.47(4H, m), 7.51-7.55(3H, m). Inter. 0.78(3H, t, J=7.4), 1.19-1.32341 65 (2H, m), 1.41-1.51(2H, m), 1.57 (M+) (1H, br), 1.89-1.99(2H, m),2.35(2H, t, J=7.4), 2.56(2H, t, J= 7.4), 3.43(2H, t, J=6.3), 3.66 (3H,s), 3.92(1H, br), 6.54(1H, d, J=2.2), 6.57(1H, d, J=2.2), 7.26-7.42(3H,m), 7.54-7.58 (2H, m). Inter. 0.79 & 0.81(3H(1:2), each t, J= 369 667.4), 1.18-1.29(2H, m), 1.31- (M+) 1.46(2H, m), 1.92-2.03(2, m),2.33-2.40(2H, m), 2.65(2H, t, J=7.4), 3.40 & 3.42(2H(1:2), each t,J=6.3), 3.67 & 3.68(3H(2:1), each s), 6.91 & 6.95(1H(2:1), each d,J=1.9), 7.32-7.44(3H, m), 7.51-7.56(2H, m), 7.79 (1/3H, br), 7.92(2/3,br), 7.03 & 8.22(1H(1:2), d, J=1.9), 8.49(2/3H, d, J=1.6), 8.83(1/3H, d,J=11.5). 51 0.75 & 0.79(3H(1:2), each t, J= 355 7.4), 1.16-1.31(2H, m),1.40- (M+) 1.53(2H, m), 1.94-2.04(2, m), 2.36-2.44(2H, m), 2.68(2H, t,J=7.4), 3.40 & 3.42(2H(1:2), each t, J=6.3), 6.91 & 6.96(1H(2:1), eachd, J=1.9), 7.30-7.44(3H, m), 7.51-7.57(2H, m), 7.96 (2/3H, br),8.14(1/3, br), 7.03 & 8.22(1H(1:2), d, J=1.9), 8.50(2/3H, d, J=1.6),8.82 (1/3H, d, J=11.5). Inter. 0.82(2H, t, J=7.4), 1.24-1.37 384 67 (2H,m), 1.43-1.53(2H, m), (MH+) 1.92-2.03(2H, m), 2.21(3H, s), 2.36(2H, t,J=7.4), 2.65(2H, t, J=7.4), 3.41(2H, t, J=6.3), 3.66(3H, s), 6.87(1H, d,J=2.2), 7.30-7.44(3H, m), 7.50-7.55 (2H, m), 7.94(1H, br), 8.20(1H, d,J=2.2). 52 0.82(2H, t, J=7.4), 1.24-1.37 370 (2H, m), 1.43-1.53(2H, m),(MH+) 1.93-2.03(2H, m), 2.21(3H, s), 2.39 (2H, t, J=7.4), 2.67(2H, t, J=7.4), 3.41(2H, t, J=6.3), 6.87 (1H, d, J=2.2), 7.30-7.44(3H, m),7.50-7.55(2H, m), 7.96(1H, br), 8.19(1H, d, J=2.2). Inter. 0.79(2H, t,J=7.4), 1.17-1.30 419 68 (2H, m), 1.42-1.52(2H, m), (M+) 1.92-2.02(2H,m), 2.36(2H, t, J=7.4), 2.65(2H, t, J=7.4), 3.09(3H, s), 3.41(2H, t,J=6.3), 3.67 (3H, s), 6.91(1H, d, J=1.9), 7.03(1H, br), 7.33-7.46(4H,m), 7.50-7.55(2H, m). 53 0.78(2H, t, J=7.4), 1.17-1.30 405 (2H, m),1.42-1.52(2H, m), (M+) 1.93-2.03(2H, m), 2.41(2H, t, J=7.4), 2.67(2H, t,J=7.4), 3.09(3H, s), 2.67(2H, t, J=7.4), 3.09(3H, s), 3.41(2H, t,J=6.3), 6.91 (1H, d, J=1.9), 7.05(1H, br), 7.33-7.54(6H, m). Inter.3.00(3H, s), 3.89(3H, s), 4.84 244 69 (2H, s), 6.91-6.97(2H, m), 7.13(M+) (1H, t, J=8.0), 7.28-7.42(3H, m), 7.52-7.56(2H, m). Inter. 3.95(3H,s), 5.85(1H, s), 201 70 6.86-7.00(3H, m), 7.31-7.46(3H, (MH+) m),7.60-7.63(2H, m). Inter. 0.74(3H, t, J=7.4), 1.14-1.28 256 71 (2H, m),1.42-1.52(2H, m), 3.66 (M+) (2H, t, J=6.6), 3.90(3H, s),6.91 (1H, dd,J=8.0, 1.6), 6.95(1H, dd, J=8.0, 1.6), 7.10(1H, t, J=8.0), 7.29-7.42(3H,m), 7.53-7.57(2H, m). Inter. 0.75(3H, t, J=7.4), 1.14-1.28 371 72 (2H,m), 1.43-1.53(2H, m), 2.77 (MH+) (2H, t, J=6.6), 3.32(2H, t, J=6.6),3.71(3H, s), 3.76(2H, t, J=6.6), 3.94(3H, s), 7.33-7.45 (3H, m),7.51-7.61(4H, m). Inter. 0.74(3H, t, J=7.4), 1.13-1.27 357 73 (2H, m),1.41-1.51(2H, m), (MH+) 1.93—2.03(2H, m), 2.36(2H, t, J=7.4), 2.64(2H,t, J=7.4), 3.62(2H, t, J=6.6), 3.67(3H, s), 3.88 (3H, s), 6.72(1H, d,J=2.2), 6.76(1H, d, J=2.2), 7.28-7.41 (3H, m), 7.52-7.56(2H, m). 540.74(3H, t, J=7.4), 1.13-1.27 342 (2H, m), 1.41-1.51(2H, m), (M+)1.94-2.04(2H, m), 2.42(2H, t, J=7.4), 2.67(2H, t, J=7.4), 3.62(2H, t,J=6.6), 3.88(3H, s), 6.72 (1H, d, J=2.2), 6.76(1H, d, J= 2.2),7.29-7.41(3H, m), 7.51-7.55(2H, m). 55 0.90(3H, t, J=7.4), 1.34-1.47 311(2H, m), 1.65-1.73(2H, m), (M+) 1.92-2.02(2H, m), 2.24(2Ht, J= 7.4),2.66(2H, t, J=7.4), 3.93(2H, t, J=6.3), 5.37(2H, br), 6.90 (1H, d,J=8.2), 7.10(1H, dd, J= 8.2, 2.2), 7.14(1H, d, J=2.2), 7.26-7.42(3H, m),7.51-7.56 (2H, m). 56 (DMSO-d6: 1.72-1.82(2H, m), 313 2.06(2H, t,J=7.4), 2.54(2H, t, (MH+) J=7.4), 4.40(2H, s), 6.72(2H, br), 6.91(1H, d,J=9.0), 7.12-7.15(4H, m), 7.29-7.46 (3H, m), 7.57-7.60(2H, m). 57(CD3OD): 1.86-2.01(4H, m), 2.23 341 (2H, t, J=7.4), 2.28(2H, t, (MH+)J=7.4), 2.63(2H, t, J=7.4, 3.96(2H, t, J=6.6), 4.88(4H, br),6.95-6.99(1H, m), 7.11-7.14 (2H, m), 7.25-7.40(3H, m), 7.48-7.50(2H, m).Inter. 1.83-1.87(4H, m), 1.91-2.01 360 74 (2H, m), 2.35(2H, t, J=7.4),(M+) 2.64(2H, t, J=7.4), 3.48(2H, t, J= 6.6), 3.66(3H, s), 3.96(2H, t,J=5.5), 6.89(1H, d, J=8.2), 7.10 (1H, dd, J=2.2, 8.2), 7.14(1H, d,J=2.2), 7.28-7.42(3H, m), 7.49-7.52(2H, m). 58 1.82-1.86(4H, m),1.91-2.01 346 (2H, m), 2.39(2H, t, J=7.4), 2.65 (M+) (2H, t, J=7.4),3.48(2H, t, J= 6.6), 3.95(2H, t, J=5.5), 6.89 (1H, d, J=8.2), 7.10(1H,dd, J= 2.2, 8.2), 7.14(1H, d, J=2.2), 7.28-7.41(3H, m), 7.49-7.52 (2H,m). Inter. 1.48(3H, d, J=6.6), 1.71-2.10 360 75 (4H, m), 2.35(2H, t,J=7.4), (M+) 2.64(2H, t, J=7.4), 3.66(3H, s), 4.03-4.19(3H, m), 6.93(1H,d, J=8.2), 7.09-7.14(2H, m), 7.28-7.42(3H, m), 7.47-7.56(2H, m). 591.47(3H, d, J=6.6), 1.91-2.16 346 (4H, m, 2.39(2H, t, J=7.4), (M+)2.65(2H, t, J=7.4), 4.02-4.18 (3H, m), 6.92(1H, d, J=8.2), 7.09-7.14(2H,m), 7.28-7.41(3H, m), 7.49-7.55(2H, m). Inter. 181-201(6H, m), 2.35(2H,t, 405 76 J=7.4), 2.63(2H, t, J=7.4), 3.35 (MH+) (2H, t, J=6.6),3.66(3H, s), 3.95(2H, t, J=6.0), 6.89(1H, d, J=8.2), 7.10(1H, dd, J=2.2,8.2), 7.14(1H, d, J=2.2), 7.28- 7.42(3H, m), 7.48-7.52 (2H, m). 601.72-2.02(6H, m), 2.39(2H, t, 390 J=7.4), 2.66(2H, t, J=7.4), 3.35 (m+)(2H, t, J=6.6), 3.95(2H, t, J=5.8), 6.89(1H, d, J=8.2), 7.10 (1H, dd,J=2.2, 8.2), 7.14 (1H, d, J=2.2), 7.28-7.42 (3H, m), 7.47-7.54(2H, m).Inter. 1.89-2.01(4H, m), 2.05-2.21 380 77 (2H, m), 2.35(2H, t, J=7.4),2.64 (M+) (2H, t, J=7.4), 3.66(3H, s), 3.97(2H, t, J=6.0), 6.88(1H, d,J=8.2), 7.11(1H, dd, J=2.2, 8.2), 7.15(1H, d, J=2.2), 7.29-7.43 (3H, m),7.47-7.51(2H, m). 61 1.89-2.02(4H, m), 2.05-2.21 366 (2H, m), 2.39(2H,t, J=7.4), (M+) 2.66(2H, t, J=7.4), 3.97(2H, t, J=6.0), 6.88(1H, d,J=8.2), 7.11 (1H, dd, J=2.2, 8.2), 7.15(1H, d, J=2.2), 7.29-7.43(3H, m),7.47-7.51(2H, m).

What is claimed is:
 1. A compound of the general formula (I) or saltthereof:

wherein n=2 or 3; R=straight or branched C₁₋₄ saturated alkyl optionallysubstituted by hydroxy, oxygen or halogen; cyclopentyl, cyclohexyl,cyclopentylmethyl, cyclohexylmethyl or (CH2)_(m)W; m=1-3; W=carboxy orCONR¹R²; R¹, R²=are together or each separately hydrogen or C₁₋₄ loweralkyl; Y=hydroxy or amino; A=hydrogen, hydroxy, methoxy, nitro or NHZ;Z=COR³ or SO₂R⁴; R³=hydrogen, C₁₋₄ saturated alkyl optionallysubstituted by hydroxy or halogen or NR⁵ ₂; R⁴=C₁₋₄ saturated alkyloptionally substituted by halogen or N R⁶ ₂; R⁵, R⁶ hydrogen or C₁₋₄lower alkyl; Q=hydrogen, hydroxy, methoxy.
 2. The compound or saltthereof according to claim 1, wherein R in the general formula (I) isn-butyl, cyclohexylmethyl, carboxymethyl or carbamoylmethyl.
 3. Thecompound or salt thereof according to claim 1, wherein the compoundrepresented by the general formula (I) is selected from the groupconsisting of 3-(2-butoxy-1,1′-biphenyl-5-yl)propionic acid;3-(2-isobutoxy-1,1′-biphenyl-5-yl)propionic acid;3-(2-pentyloxy-1,1′-biphenyl-5-yl)propionic acid;3-(2-cyclopentyloxy-1,1′-biphenyl-5-yl)propionic acid;3-(2-cyclohexyloxy-1,1′-biphenyl-5-yl)propionic acid;3-(2-cyclopentylmethyloxy-1,1′-biphenyl-5-yl)propionic acid;3-(2-cyclohexylmethyloxy-1,1′-biphenyl-5-yl)propionic acid;3-[2-(2-hydroxybutyloxy)-1,1′-biphenyl-5-yl]propionic acid;3-[2-(2-oxobutyloxy)-1,1′-biphenyl-5-yl]propionic acid;3-(2-carboxymethyloxy-1,1′-biphenyl-5-yl)propionic acid;3-(2-carbamoylmethyloxy-1,1′-biphenyl-5-yl)propionic acid;3-(2-butoxy-3-nitro-1,1′-biphenyl-5-yl)propionic acid;3-(3-acetylamino-2-butoxy-1,1′-biphenyl-5-yl)propionic acid;3-(2-butoxy-3-methylsulfonylamino-1,1′-biphenyl-5-yl)propionic acid;3-(3-acetylamino-2-cyclohexylmethyloxy-1,1′-biphenyl-5-yl)propionicacid;3-(2-cyclohexylmethyloxy-3-methylsulfonylamino-1,1′-biphenyl-5-yl)propionicacid;3-(2-cyclohexylmethyloxy-3-hydroxyacetylamino-1,1′-biphenyl-5-yl)propionicacid;3-[2-cyclohexylmethyloxy-3-(N,N-dimethylcarbamoylamino)-1,1′-biphenyl-5-yl]propionicacid;3-[2-cyclohexylmethyloxy-3-(N,N-dimethylsulfamoylamino)-1,1′-biphenyl-5-yl]propionicacid;3-(3-carbamoylamino-2-cyclohexylmethyloxy-1,1′-biphenyl-5-yl)propionicacid; 3-(2-cyclohexylmethyloxy-3-methoxy-1,1′-biphenyl-5-yl)propionicacid; 3-(2-cyclohexylmethyloxy-3-hydroxy-1,1′-biphenyl-5-yl)propionicacid; 3-(2-cyclohexylmethyloxy-4′-hydroxy-1,1′-biphenyl-5-yl)propionicacid; 3-(2-cyclohexylmethyloxy-4′-methoxy-1,1′-biphenyl-5-yl)propionicacid; 3-(2-cyclohexylmethyloxy-1,1′-biphenyl-5-yl)propionamide;4-(2-butoxy-1,1′-biphenyl-5-yl)butyric acid;4-(2-isobutoxy-1,1′-biphenyl-5-yl)butyric acid;4-[2-(1-methylpropyloxy)-1,1′-biphenyl-5-yl]butyric acid;4-(2-pentyloxy-1,1′-biphenyl-5-yl)butyric acid;4-[2-(1-methylbutyloxy)-1,1′-biphenyl-5-yl]butyric acid;4-[2-(2-methylbutyloxy)-1,1′-biphenyl-5-yl]butyric acid;4-(2-isopentyloxy-1,1′-biphenyl-5-yl)butyric acid;4-(2-cyclopentyloxy-1,1′-biphenyl-5-yl)butyric acid;4-(2-cyclohexyloxy-1,1′-biphenyl-5-yl)butyric acid;4-(2-cyclopentylmethyloxy-1,1′-biphenyl-5-yl)butyric acid;4-(2-cyclohexylmethyloxy-1,1′-biphenyl-5-yl)butyric acid;4-[2-(4-hydroxybutyloxy)-1,1′-biphenyl-5-yl]butyric acid;4-[2-(3-hydroxybutyloxy)-1,1′-biphenyl-5-yl]butyric acid;4-[2-(2-hydroxybutyloxy)-1,1′-biphenyl-5-yl]butyric acid;4-(2-carboxymethyloxy-1,1′-biphenyl-5-yl)butyric acid;4-[2-(2-carboxyethyloxy)-1,1′-biphenyl-5-yl)butyric acid;4-[2-(3-carboxypropyloxy)-1,1′-biphenyl-5-yl]butyric acid;4-(2-carbamoylmethyloxy-1,1′-biphenyl-5-yl)butyric acid;4-[2-(N,N-dimethylcarbamoylmethyloxy)-1,1′-biphenyl-5-yl]butyric acid;4-[2-(N,N-diethylcarbamoylmethyloxy)-1,1′-biphenyl-5-yl]butyric acid;4-(2-butoxy-3-nitro-1,1′-biphenyl-5-yl)butyric acid;4-(2-butoxy-3-formylamino-1,1′-biphenyl-5-yl)butyric acid;4-(3-acetylamino-2-butoxy-1,1′-biphenyl-5-yl)butyric acid;4-(2-butoxy-3-methylsulfonylamino-1,1′-biphenyl-5-yl)butyric acid;4-(2-butoxy-3-methoxy-1,1′-biphenyl-5-yl)butyric acid;4-(2-butoxy-1,1′-biphenyl-5-yl)butyramide;4-(2-carbamoylmethyloxy-1,1′-biphenyl-5-yl)butyramide;4-[2-(3-carbamoylpropyloxy)-1,1′-biphenyl-5-yl]butyramide;4-[2-(4-chlorobutyloxy)-1,1′-biphenyl-5-yl]butyric acid;4-[2-(3-chlorobutyloxy)-1,1′-biphenyl-5-yl]butyric acid;4-[2-(4-bromobutyloxy)-1,1′-biphenyl-5-yl]butyric acid and4-[2-(4,4,4-trifluorobutyloxy)-1,1′-biphenyl-5-yl]butyric acid.
 4. Apharmaceutical composition comprising at least one of compounds orpharmacologically acceptable salt thereof according to claim 1 and apharmaceutically acceptable carrier.
 5. The pharmaceutical compositionaccording to claim 4 wherein the pharmaceutical composition is IgEproduction suppressor or agent for prevention or treatment of allergicdisease involved in IgE antibody.
 6. The pharmaceutical compositionaccording to claim 4 wherein the pharmaceutical composition is agent fortreatment or prevention of bronchial asthma, allergic rhinitis, atopicdermatitis or allergic conjunctivitis.